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Entry
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- *601205 - SIX HOMEOBOX 1; SIX1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601205</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601205">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000126778;t=ENST00000645694" 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=6495" 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=601205" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000126778;t=ENST00000645694" 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_001425142,NM_005982" 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_005982" 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=601205" 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=03125&isoform_id=03125_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/SIX1" 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/1246761,2495290,5174681,12744793,14250808,30583005,60496343,119601190,119601191,2604071525" 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/Q15475" 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=6495" 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=ENSG00000126778;t=ENST00000645694" 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=SIX1" 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=SIX1" 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+6495" 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/SIX1" 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:6495" 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/6495" 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=chr14&hgg_gene=ENST00000645694.3&hgg_start=60643421&hgg_end=60649477&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:10887" 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:10887" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/six1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601205[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=601205[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/SIX1/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/ENSG00000126778" 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=SIX1" 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=SIX1" 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=SIX1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SIX1&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/PA35787" 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:10887" 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/FBgn0003460.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:102780" 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/SIX1#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:102780" 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/6495/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6495" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000454;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000454 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000455;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000455 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-2308" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6495" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=SIX1&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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</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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601205
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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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SIX HOMEOBOX 1; SIX1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 1
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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=SIX1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SIX1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/14/287?start=-3&limit=10&highlight=287">14q23.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:60643421-60649477&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'})">14:60,643,421-60,649,477</a> </span>
|
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<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
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=608389,605192" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
|
</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/287?start=-3&limit=10&highlight=287">
|
|
14q23.1
|
|
</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Branchiootic syndrome 3
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/608389"> 608389 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</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">
|
|
Deafness, autosomal dominant 23
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/entry/605192"> 605192 </a>
|
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|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</span>
|
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<p>The vertebrate SIX genes are homologs of the Drosophila 'sine oculis' (so) gene, which is expressed primarily in the developing visual system of the fly. Members of the SIX gene family encode proteins that are characterized by a divergent DNA-binding homeodomain and an upstream SIX domain, which may be involved both in determining DNA-binding specificity and in mediating protein-protein interactions. Genes in the SIX family have been shown to play roles in vertebrate and insect development or have been implicated in maintenance of the differentiated state of tissues (summary by <a href="#3" class="mim-tip-reference" title="Boucher, C. A., Winchester, C. L., Hamilton, G. M., Winter, A. D., Johnson, K. J., Bailey, M. E. S. <strong>Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2.</strong> Gene 247: 145-151, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10773454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10773454</a>] [<a href="https://doi.org/10.1016/s0378-1119(00)00105-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10773454">Boucher et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10773454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Boucher, C. A., Carey, N., Edwards, Y. H., Siciliano, M. J., Johnson, K. J. <strong>Cloning of the human SIX1 gene and its assignment to chromosome 14.</strong> Genomics 33: 140-142, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8617500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8617500</a>] [<a href="https://doi.org/10.1006/geno.1996.0172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8617500">Boucher et al. (1996)</a> cloned and sequenced a human SIX1 cDNA and showed by Northern blotting that it is expressed in adult skeletal muscle. The cDNA sequence and predicted protein sequence of the human and mouse genes are highly homologous, with 98% similarity over the entire predicted amino acid sequence. During mouse limb development at embryonic day 11.5, Six1 and Six2 are expressed distally over the posterior and anterior limb regions, respectively. However, by E14.5, expression of Six1 and Six2 is detected flanking the phalanges in domains corresponding to the anterior-posterior and dorsoventral axes, respectively. Six1 is also weakly expressed in skeletal muscles of the head and body during late development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8617500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Ford, H. L., Kabingu, E. N., Bump, E. A., Mutter, G. L., Pardee, A. B. <strong>Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.</strong> Proc. Nat. Acad. Sci. 95: 12608-12613, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9770533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9770533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9770533[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.95.21.12608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9770533">Ford et al. (1998)</a> cloned the human SIX1 homeobox gene from late S phase mammary carcinoma cells and demonstrated that overexpression of SIX1 leads to an abrogation of the DNA damage-induced G2 cell cycle checkpoint. In addition, they found that overexpression of SIX1 occurs in a large percentage of mammary carcinomas and correlates strongly with metastatic breast disease. It appeared that studies of several cancer cell lines suggested that SIX1 may be overexpressed in multiple types of tumors. Thus, the studies linked SIX1 to the cell cycle as well as to tumor progression and provided further evidence that 'master regulators' involved in development may contribute to tumorigenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9770533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Ridgeway, A. G., Skerjanc, I. S. <strong>Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2.</strong> J. Biol. Chem. 276: 19033-19039, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11262400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11262400</a>] [<a href="https://doi.org/10.1074/jbc.M011491200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11262400">Ridgeway and Skerjanc (2001)</a> induced myogenesis in a mouse pluripotent stem cell line. Myogenesis was associated with increased expression of Pax3 (<a href="/entry/606597">606597</a>), followed by expression of the transcription factor Six1, its cofactor Eya2 (<a href="/entry/601654">601654</a>), and the transcription factor Mox1 (<a href="/entry/600147">600147</a>), prior to the induction of MyoD (<a href="/entry/159970">159970</a>) and myogenin (Myog; <a href="/entry/159980">159980</a>) expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11262400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S., Merlino, G. <strong>Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.</strong> Nature Med. 10: 175-181, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14704789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14704789</a>] [<a href="https://doi.org/10.1038/nm966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14704789">Yu et al. (2004)</a> established highly and poorly metastatic rhabdomyosarcoma cell lines derived from a transgenic mouse model overexpressing Hgf/Sf (<a href="/entry/142409">142409</a>) and deficient for Ink4a/Arf (<a href="/entry/600160">600160</a>), in which skeletal muscle tumors reminiscent of those in embryonic rhabdomyosarcoma (<a href="/entry/268210">268210</a>) arise with very high penetrance and short latency (<a href="#21" class="mim-tip-reference" title="Sharp, R., Recio, J. A., Jhappan, C., Otsuka, T., Liu, S., Yu, Y., Liu, W., Anver, M., Navid, F., Helman, L. J., DePinho, R. A., Merlino, G. <strong>Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.</strong> Nature Med. 8: 1276-1280, 2002. Note: Erratum: Nature Med. 9: 146 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368906</a>] [<a href="https://doi.org/10.1038/nm787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12368906">Sharp et al., 2002</a>). <a href="#22" class="mim-tip-reference" title="Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S., Merlino, G. <strong>Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.</strong> Nature Med. 10: 175-181, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14704789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14704789</a>] [<a href="https://doi.org/10.1038/nm966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14704789">Yu et al. (2004)</a> then used cDNA microarray analysis of these cell lines to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that ezrin, encoded by Vil2 (<a href="/entry/123900">123900</a>), and Six1 have essential roles in determining the metastatic fate of rhabdomyosarcoma cells. VIL2 and SIX1 expression was enhanced in human rhabdomyosarcoma tissue, significantly correlating with clinical stage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14704789+12368906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X. <strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong> Hum. Molec. Genet. 10: 2775-2781, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734542</a>] [<a href="https://doi.org/10.1093/hmg/10.24.2775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11734542">Buller et al. (2001)</a> analyzed the functional importance of Eya (EYA1; <a href="/entry/601653">601653</a>) domain missense mutations with respect to protein complex formation and cellular localization. Previously described point mutations did not alter protein localization; however, 3 mutations (glu330 to lys, <a href="/entry/601653#0009">601653.0009</a>; ser454 to pro, <a href="/entry/601653#0012">601653.0012</a>; and leu472 to arg, <a href="/entry/601653#0013">601653.0013</a>) disrupted interactions between Eya and Six1 in both yeast and mammalian cells. Binding to Six2 (<a href="/entry/604994">604994</a>) was not impeded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Grifone, R., Laclef, C., Spitz, F., Lopez, S., Demignon, J., Guidotti, J.-E., Kawakami, K., Xu, P.-X., Kelly, R., Petrof, B. J., Daegelen, D., Concordet, J.-P., Maire, P. <strong>Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.</strong> Molec. Cell. Biol. 24: 6253-6267, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15226428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15226428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15226428[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/10.1128/MCB.24.14.6253-6267.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15226428">Grifone et al. (2004)</a> found that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 accumulated preferentially in the nuclei of fast-twitch muscles. Forced coexpression of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition to a fast-twitch fiber type, with activation of fast-twitch fiber-specific genes and a switch toward glycolytic metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15226428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>SALL1 (<a href="/entry/602218">602218</a>) is a transcription factor that has a critical role in kidney development. Using gel retardation assays, reporter gene assays, and mutation analysis, <a href="#5" class="mim-tip-reference" title="Chai, L., Yang, J., Di, C., Cui, W., Kawakami, K., Lai, R., Ma, Y. <strong>Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development.</strong> J. Biol. Chem. 281: 18918-18926, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670092</a>] [<a href="https://doi.org/10.1074/jbc.M600180200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670092">Chai et al. (2006)</a> showed that SIX1 directly bound the SALL1 promoter and induced SALL1 expression in a dose-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16670092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="McCoy, E. L., Iwanaga, R., Jedlicka, P., Abbey, N.-S., Chodosh, L. A., Heichman, K. A., Welm, A. L., Ford, H. L. <strong>Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.</strong> J. Clin. Invest. 119: 2663-2677, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726883</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726883[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726883">McCoy et al. (2009)</a> found that misexpression of human SIX1 in adult mouse mammary gland epithelium induced tumors of multiple histologic subtypes in a dose-dependent manner. Most SIX1-induced tumors underwent an epithelial-to-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt (see <a href="/entry/164820">164820</a>) signaling, including cyclin D1 (CCND1; <a href="/entry/168461">168461</a>). SIX1 promoted a stem/progenitor cell phenotype in mouse mammary gland and in SIX1-dependent mammary tumors. Coexpression of SIX1 and cyclin D1 was detected in several human breast cancers and was predictive of poor prognosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19726883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Independently, <a href="#13" class="mim-tip-reference" title="Micalizzi, D. S., Christensen, K. L., Jedlicka, P., Coletta, R. D., Baron, A. E., Harrell, J. C., Horwitz, K. B., Billheimer, D., Heichman, K. A., Welm, A. L., Schiemann, W. P., Ford, H. L. <strong>The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.</strong> J. Clin. Invest. 119: 2678-2690, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726885</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726885[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726885">Micalizzi et al. (2009)</a> showed that SIX1 overexpression in human and mouse mammary epithelial cells induced EMT and metastasis, both of which were dependent on the ability of SIX1 to activate TGF-beta (TGFB1; <a href="/entry/190180">190180</a>) signaling. Breast cancer patients whose tumors overexpressed SIX1 had a shortened time to relapse and metastasis and an overall decrease in survival. Similarly, overexpression of SIX1 correlated with adverse outcomes in a number of other cancers, including brain, cervical, prostate, colon, kidney, and liver. <a href="#13" class="mim-tip-reference" title="Micalizzi, D. S., Christensen, K. L., Jedlicka, P., Coletta, R. D., Baron, A. E., Harrell, J. C., Horwitz, K. B., Billheimer, D., Heichman, K. A., Welm, A. L., Schiemann, W. P., Ford, H. L. <strong>The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.</strong> J. Clin. Invest. 119: 2678-2690, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726885</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726885[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI37815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726885">Micalizzi et al. (2009)</a> concluded that SIX1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19726885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Delgado-Olguin, P., Huang, Y., Li, X., Christodoulou, D., Seidman, C. E., Seidman, J. G., Tarakhovsky, A., Bruneau, B. G. <strong>Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.</strong> Nature Genet. 44: 343-347, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22267199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22267199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22267199[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.1068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22267199">Delgado-Olguin et al. (2012)</a> found that conditional deletion of Ezh2 (<a href="/entry/601573">601573</a>) in mouse anterior heart field resulted in right cardiac hypertrophy and fibrosis after birth. Gene expression profiling of Ezh2-knockout hearts revealed derepression of Six1, with concomitant activation of Six1-dependent skeletal muscle-specific genes. Overexpression of Six1 in cultured neonatal mouse cardiomyocytes resulted in hypertrophy comparable to that induced by the hypertrophic agonist endothelin-1 (EDN1; <a href="/entry/131240">131240</a>). Knockdown of Six1 in Ezh2-knockout hearts completely rescued the cardiac phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22267199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Liu, Z., Mar, K. B., Hanners, N. W., Perelman, S. S., Kanchwala, M., Xing, C., Schoggins, J. W., Alto, N. M. <strong>A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-kappa-B.</strong> Nature 568: 249-253, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30894749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30894749</a>] [<a href="https://doi.org/10.1038/s41586-019-1041-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30894749">Liu et al. (2019)</a> showed that the SIX homolog family transcription factors SIX1 and SIX2 (<a href="/entry/604994">604994</a>) are integral components of the noncanonical NF-kappa-B (see <a href="/entry/164011">164011</a>) signaling cascade. The developmentally silenced SIX proteins were reactivated in differentiated macrophages by NIK (<a href="/entry/604655">604655</a>)-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 targeted a subset of inflammatory gene promoters and directly inhibited the trans-activation function of the transcription factors RELA (<a href="/entry/164014">164014</a>) and RELB (<a href="/entry/604758">604758</a>) in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS (see <a href="/entry/190070">190070</a>)/P53 (<a href="/entry/191170">191170</a>)-driven non-small-cell lung carcinomas from inflammatory cell death induced by small molecule activators of the noncanonical NF-kappa-B pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30894749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Gallardo, M. E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M. J., Brunner, H. G., Bovolenta, P., Rodriguez de Cordoba, S. <strong>Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies.</strong> Genomics 61: 82-91, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10512683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10512683</a>] [<a href="https://doi.org/10.1006/geno.1999.5916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10512683">Gallardo et al. (1999)</a> performed phylogenetic analysis of SIX gene family members and presented a model for the origin and evolution of SIX gene clusters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10512683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rodent/human somatic cell hybrid panel, <a href="#2" class="mim-tip-reference" title="Boucher, C. A., Carey, N., Edwards, Y. H., Siciliano, M. J., Johnson, K. J. <strong>Cloning of the human SIX1 gene and its assignment to chromosome 14.</strong> Genomics 33: 140-142, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8617500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8617500</a>] [<a href="https://doi.org/10.1006/geno.1996.0172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8617500">Boucher et al. (1996)</a> mapped the human SIX1 gene to chromosome 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8617500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. <strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong> Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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.0308475101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141091">Ruf et al. (2004)</a> located the SIX1, SIX4 (<a href="/entry/606342">606342</a>), and SIX6 (<a href="/entry/606326">606326</a>) genes, which play a role in the EYA-SIX-PAX (see <a href="/entry/167411">167411</a>) hierarchy of regulatory genes for the embryonic development of ear, kidney, and other organs, within a 33-Mb critical interval on chromosome 14q23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15141091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Oliver, G., Wehr, R., Jenkins, N. A., Copeland, N. G., Cheyette, B. N. R., Hartenstein, V., Zipursky, S. L., Gruss, P. <strong>Homeobox genes and connective tissue patterning.</strong> Development 121: 693-705, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7720577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7720577</a>] [<a href="https://doi.org/10.1242/dev.121.3.693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7720577">Oliver et al. (1995)</a> mapped the mouse Six1 gene to the central region of chromosome 12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7720577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Branchiootorenal syndrome (see <a href="/entry/113650">113650</a>) is an autosomal dominant disorder characterized by hearing loss, branchial cleft fistulas or cysts, and renal dysplasia. Branchiootic syndrome (see <a href="/entry/602588">602588</a>) is a related disorder without renal anomalies. <a href="#17" class="mim-tip-reference" title="Ruf, R. G., Berkman, J., Wolf, M. T. F., Nurnberg, P., Gattas, M., Ruf, E.-M., Hyland, V., Kromberg, J., Glass, I., Macmillan, J., Otto, E., Nurnberg, G., Lucke, B., Hennies, H. C., Hildebrandt, F. <strong>A gene locus for branchio-otic syndrome maps to chromosome 14q21.3-q24.3.</strong> J. Med. Genet. 40: 515-519, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843324</a>] [<a href="https://doi.org/10.1136/jmg.40.7.515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843324">Ruf et al. (2003)</a> mapped a locus for the BOR/BO syndrome (BOS3; <a href="/entry/608389">608389</a>) to chromosome 14q23. By direct sequencing of SIX1 exons, they identified 2 different mutations in the SIX1 gene in 3 kindreds with BOS3: tyr129 to cys (Y129C; <a href="#0001">601205.0001</a>) and arg110 to trp (R110W; <a href="#0002">601205.0002</a>). Both mutations are crucial for EYA1-SIX1 interaction, and the Y129C mutation, which is within the homeodomain region, is essential for specific SIX1-DNA binding. In a member of a fourth family, previously reported by <a href="#19" class="mim-tip-reference" title="Salam, A. A., Hafner, F. M., Linder, T. E., Spillmann, T., Schinzel, A. A., Leal, S. M. <strong>A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred.</strong> Am. J. Hum. Genet. 66: 1984-1988, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777717</a>] [<a href="https://doi.org/10.1086/302931" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10777717">Salam et al. (2000)</a> with DFNA23 (<a href="/entry/605192">605192</a>), <a href="#18" class="mim-tip-reference" title="Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. <strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong> Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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.0308475101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141091">Ruf et al. (2004)</a> identified a 3-bp deletion in the SIX1 gene (<a href="#0003">601205.0003</a>). In addition to deafness, the patient had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure, suggesting that this family may have BOR/BO syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12843324+15141091+10777717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome, <a href="#20" class="mim-tip-reference" title="Sanggaard, K. M., Rendtorff, N. D., Kjaer, K. W., Eiberg, H., Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K. O., Lage, K., Tranebjaerg, L. <strong>Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.</strong> Europ. J. Hum. Genet. 15: 1121-1131, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17637804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17637804</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17637804">Sanggaard et al. (2007)</a> identified heterozygosity for a missense mutation in the SIX1 gene (<a href="#0004">601205.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17637804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 direct sequencing of the SIX1 gene in an affected member of a Tunisian family with autosomal dominant hearing impairment and preauricular pits mapping to chromosome 14q23, <a href="#14" class="mim-tip-reference" title="Mosrati, M. A., Hammami, B., Rebeh, I. B., Ayadi, L., Dhouib, L., Ben Mahfoudh, K., Hakim, B., Charfeddine, I., Mnif, J., Ghorbel, A., Masmoudi, S. <strong>A novel dominant mutation in SIX1, affecting a highly conserved residue, result (sic) in only auditory defects in humans.</strong> Europ. J. Med. Genet. 54: e484-e488, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700001</a>] [<a href="https://doi.org/10.1016/j.ejmg.2011.06.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700001">Mosrati et al. (2011)</a> identified a heterozygous missense mutation (E125K; <a href="#0005">601205.0005</a>) that segregated with the phenotype in family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al. (2003)</a> reported that Six1 is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya factors. <a href="#10" class="mim-tip-reference" title="Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G. <strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong> Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628042</a>] [<a href="https://doi.org/10.1038/nature02083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628042">Li et al. (2003)</a> demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach (<a href="/entry/603803">603803</a>) from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog and in double knockouts for MyoD/Myf5 (<a href="/entry/159990">159990</a>) and Pax3/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P. <strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong> Dev. Biol. 328: 285-296, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389353[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.ydbio.2009.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19389353">Bosman et al. (2009)</a> reported 'catweasel' (cwe), an N-ethyl-N-nitrosourea-induced mutation that caused mild headbobbing in heterozygous cwe/+ mice. These mice lacked the eminentium cruciatum in the posterior crista and had extra inner hair cells in the organ of Corti. <a href="#1" class="mim-tip-reference" title="Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P. <strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong> Dev. Biol. 328: 285-296, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389353[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.ydbio.2009.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19389353">Bosman et al. (2009)</a> identified cwe as a 411A-G transition in exon 1 of the Six1 gene, resulting in a glu135-to-gly (E135G) substitution of a highly conserved residue in the N-terminal part of the Six1 homeobox domain. The mutation did not alter Six1 expression, but it was predicted to destabilize binding of Six1 to DNA. <a href="#1" class="mim-tip-reference" title="Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P. <strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong> Dev. Biol. 328: 285-296, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389353[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.ydbio.2009.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19389353">Bosman et al. (2009)</a> observed that the cwe/+ phenotype was less severe than the Six1 +/- phenotype. Homozygous cwe/cwe mice had a more severe phenotype than cwe/+ mice that resembled branchiootorenal syndrome, with extreme headshaking and circling behavior. Cwe/cwe animals appeared normal in most behavior tests, but they were deaf and lacked contact righting response and Preyer reflex. They also had severe vestibular abnormalities and defects in the inner and middle ear, lacked most sensory hair cells, and showed renal defects. Cwe/cwe embryos showed defects in sensory patch development as early as embryonic day 10.5. Bmp4 (<a href="/entry/112262">112262</a>), Jag1 (<a href="/entry/601920">601920</a>), and Sox2 (<a href="/entry/184429">184429</a>) expression was largely absent at early stages of sensory development, and NeuroD (see <a href="/entry/601724">601724</a>) expression was reduced in developing vestibuloacoustic ganglion. <a href="#1" class="mim-tip-reference" title="Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P. <strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong> Dev. Biol. 328: 285-296, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389353[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.ydbio.2009.01.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19389353">Bosman et al. (2009)</a> noted that htu/+ mice with a mutation in the Jag1 gene show a phenotype similar to cwe/+ mice. Experiments with cwe/+, htu/+, and double-heterozygous cwe/+ htu/+ mice suggested that Six1 acts upstream of Jag1 in the Notch signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19389353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=601205[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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<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> rs104894478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894478;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/rs104894478?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=rs104894478" 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=rs104894478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of the kindred in which <a href="#17" class="mim-tip-reference" title="Ruf, R. G., Berkman, J., Wolf, M. T. F., Nurnberg, P., Gattas, M., Ruf, E.-M., Hyland, V., Kromberg, J., Glass, I., Macmillan, J., Otto, E., Nurnberg, G., Lucke, B., Hennies, H. C., Hildebrandt, F. <strong>A gene locus for branchio-otic syndrome maps to chromosome 14q21.3-q24.3.</strong> J. Med. Genet. 40: 515-519, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843324</a>] [<a href="https://doi.org/10.1136/jmg.40.7.515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843324">Ruf et al. (2003)</a> mapped branchiootic syndrome-3 (BOS3; <a href="/entry/608389">608389</a>) to 14q, <a href="#18" class="mim-tip-reference" title="Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. <strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong> Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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.0308475101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141091">Ruf et al. (2004)</a> identified heterozygosity for a 386A-G transition in exon 1 of the SIX1 gene, resulting in a tyr129-to-cys (Y129C) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12843324+15141091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008807 OR RCV002262561 OR RCV002512919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008807, RCV002262561, RCV002512919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008807...</a>
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<p>In affected members of 2 families with branchiootic syndrome-3 (BOS3; <a href="/entry/608389">608389</a>), <a href="#18" class="mim-tip-reference" title="Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. <strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong> Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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.0308475101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141091">Ruf et al. (2004)</a> identified heterozygosity for a 328C-T transition in exon 1 of the SIX1 gene, resulting in an arg110-to-trp (R110W) mutation. Branchial and otic defects were present in affected members of both families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15141091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356460 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356460;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=rs80356460" 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=rs80356460" 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=RCV000008808 OR RCV000020636 OR RCV002512920 OR RCV003162220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008808, RCV000020636, RCV002512920, RCV003162220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008808...</a>
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<p>In a member of a family previously reported by <a href="#19" class="mim-tip-reference" title="Salam, A. A., Hafner, F. M., Linder, T. E., Spillmann, T., Schinzel, A. A., Leal, S. M. <strong>A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred.</strong> Am. J. Hum. Genet. 66: 1984-1988, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10777717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10777717</a>] [<a href="https://doi.org/10.1086/302931" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10777717">Salam et al. (2000)</a> with DFNA23 (<a href="/entry/605192">605192</a>), <a href="#18" class="mim-tip-reference" title="Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. <strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong> Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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.0308475101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141091">Ruf et al. (2004)</a> identified heterozygosity for a 3-bp deletion (397delGGA) in the SIX1 gene, resulting in the deletion of glutamic acid at position 133. In addition to deafness, the patient had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure, suggesting that this family may have BOR/BO syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15141091+10777717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 BRANCHIOOTIC SYNDROME 3</strong>
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SIX1, TRP122ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909770 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909770;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=rs121909770" 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=rs121909770" 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=RCV000008809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008809</a>
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<p>In 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome-3 (BOS3; <a href="/entry/608389">608389</a>), <a href="#20" class="mim-tip-reference" title="Sanggaard, K. M., Rendtorff, N. D., Kjaer, K. W., Eiberg, H., Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K. O., Lage, K., Tranebjaerg, L. <strong>Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.</strong> Europ. J. Hum. Genet. 15: 1121-1131, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17637804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17637804</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17637804">Sanggaard et al. (2007)</a> identified heterozygosity for a 364T-A transversion in exon 1 of the SIX1 gene, resulting in a trp122-to-arg (W122R) substitution at a conserved residue. The mutation was not found in unaffected family members or in 140 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17637804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DEAFNESS, AUTOSOMAL DOMINANT 23</strong>
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SIX1, GLU125LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044960 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044960;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=rs797044960" 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=rs797044960" 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=RCV000190433 OR RCV001852527 OR RCV002478668" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190433, RCV001852527, RCV002478668" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190433...</a>
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<p>By direct sequencing of the SIX1 gene in an affected member of a Tunisian family with autosomal dominant hearing impairment and preauricular pits mapping to 14q23, <a href="#14" class="mim-tip-reference" title="Mosrati, M. A., Hammami, B., Rebeh, I. B., Ayadi, L., Dhouib, L., Ben Mahfoudh, K., Hakim, B., Charfeddine, I., Mnif, J., Ghorbel, A., Masmoudi, S. <strong>A novel dominant mutation in SIX1, affecting a highly conserved residue, result (sic) in only auditory defects in humans.</strong> Europ. J. Med. Genet. 54: e484-e488, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700001</a>] [<a href="https://doi.org/10.1016/j.ejmg.2011.06.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700001">Mosrati et al. (2011)</a> identified a heterozygous c.373G-A transition, predicted to result in a glu125-to-lys (E125K) substitution at a conserved residue. Segregation of the variant with the phenotype was confirmed by PCR restriction fragment length polymorphism. The glu125 residue is located in the N-terminal arm and is likely to affect DNA binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Bosman2009" class="mim-anchor"></a>
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Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P.
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<strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong>
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Dev. Biol. 328: 285-296, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19389353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19389353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19389353[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=19389353" 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.ydbio.2009.01.030" target="_blank">Full Text</a>]
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<a id="Boucher1996" class="mim-anchor"></a>
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Boucher, C. A., Carey, N., Edwards, Y. H., Siciliano, M. J., Johnson, K. J.
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<strong>Cloning of the human SIX1 gene and its assignment to chromosome 14.</strong>
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Genomics 33: 140-142, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8617500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8617500</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8617500" 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.1996.0172" target="_blank">Full Text</a>]
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<a id="Boucher2000" class="mim-anchor"></a>
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Boucher, C. A., Winchester, C. L., Hamilton, G. M., Winter, A. D., Johnson, K. J., Bailey, M. E. S.
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<strong>Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2.</strong>
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Gene 247: 145-151, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10773454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10773454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10773454" 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/s0378-1119(00)00105-0" target="_blank">Full Text</a>]
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Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X.
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<strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong>
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Hum. Molec. Genet. 10: 2775-2781, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734542" 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/10.24.2775" target="_blank">Full Text</a>]
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Chai, L., Yang, J., Di, C., Cui, W., Kawakami, K., Lai, R., Ma, Y.
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<strong>Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development.</strong>
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J. Biol. Chem. 281: 18918-18926, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670092</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16670092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M600180200" target="_blank">Full Text</a>]
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Delgado-Olguin, P., Huang, Y., Li, X., Christodoulou, D., Seidman, C. E., Seidman, J. G., Tarakhovsky, A., Bruneau, B. G.
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<strong>Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.</strong>
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Nature Genet. 44: 343-347, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22267199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22267199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22267199[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=22267199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.1068" target="_blank">Full Text</a>]
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<a id="Ford1998" class="mim-anchor"></a>
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Ford, H. L., Kabingu, E. N., Bump, E. A., Mutter, G. L., Pardee, A. B.
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<strong>Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.</strong>
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Proc. Nat. Acad. Sci. 95: 12608-12613, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9770533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9770533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9770533[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=9770533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.95.21.12608" target="_blank">Full Text</a>]
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<a id="Gallardo1999" class="mim-anchor"></a>
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Gallardo, M. E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M. J., Brunner, H. G., Bovolenta, P., Rodriguez de Cordoba, S.
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<strong>Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies.</strong>
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Genomics 61: 82-91, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10512683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10512683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10512683" 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.1999.5916" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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<strong>Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.</strong>
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[<a href="https://doi.org/10.1128/MCB.24.14.6253-6267.2004" target="_blank">Full Text</a>]
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<strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong>
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[<a href="https://doi.org/10.1038/nature02083" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1041-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI37691" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI37815" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2011.06.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.121.3.693" target="_blank">Full Text</a>]
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<strong>Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11262400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11262400</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11262400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M011491200" target="_blank">Full Text</a>]
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<a id="Ruf2003" class="mim-anchor"></a>
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Ruf, R. G., Berkman, J., Wolf, M. T. F., Nurnberg, P., Gattas, M., Ruf, E.-M., Hyland, V., Kromberg, J., Glass, I., Macmillan, J., Otto, E., Nurnberg, G., Lucke, B., Hennies, H. C., Hildebrandt, F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843324</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843324" 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/10.1136/jmg.40.7.515" target="_blank">Full Text</a>]
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<a id="Ruf2004" class="mim-anchor"></a>
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Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141091</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15141091[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=15141091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0308475101" target="_blank">Full Text</a>]
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Salam, A. A., Hafner, F. M., Linder, T. E., Spillmann, T., Schinzel, A. A., Leal, S. M.
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<strong>A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred.</strong>
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[<a href="https://doi.org/10.1086/302931" target="_blank">Full Text</a>]
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Sanggaard, K. M., Rendtorff, N. D., Kjaer, K. W., Eiberg, H., Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K. O., Lage, K., Tranebjaerg, L.
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[<a href="https://doi.org/10.1038/sj.ejhg.5201900" target="_blank">Full Text</a>]
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<a id="Sharp2002" class="mim-anchor"></a>
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Sharp, R., Recio, J. A., Jhappan, C., Otsuka, T., Liu, S., Yu, Y., Liu, W., Anver, M., Navid, F., Helman, L. J., DePinho, R. A., Merlino, G.
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<strong>Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12368906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12368906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12368906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm787" target="_blank">Full Text</a>]
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<a id="Yu2004" class="mim-anchor"></a>
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Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S., Merlino, G.
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<strong>Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14704789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14704789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14704789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm966" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 08/20/2019
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Patricia A. Hartz - updated : 8/24/2015<br>Joanna S. Amberger - updated : 8/21/2015<br>Patricia A. Hartz - updated : 3/19/2012<br>Patricia A. Hartz - updated : 1/6/2011<br>Marla J. F. O'Neill - updated : 7/18/2008<br>Patricia A. Hartz - updated : 12/5/2006<br>Victor A. McKusick - updated : 7/8/2004<br>Ada Hamosh - updated : 1/30/2004<br>Ada Hamosh - updated : 12/31/2003<br>Patricia A. Hartz - updated : 4/1/2003<br>George E. Tiller - updated : 6/7/2002<br>Patti M. Sherman - updated : 5/23/2000<br>Victor A. McKusick - updated : 11/3/1998
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Victor A. McKusick : 4/16/1996
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alopez : 08/20/2019
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carol : 08/16/2019<br>carol : 08/15/2019<br>carol : 09/16/2016<br>mgross : 08/26/2015<br>mcolton : 8/24/2015<br>carol : 8/23/2015<br>carol : 8/21/2015<br>carol : 8/6/2015<br>carol : 4/10/2015<br>alopez : 12/5/2014<br>alopez : 12/11/2012<br>terry : 11/28/2012<br>mgross : 3/19/2012<br>terry : 3/19/2012<br>mgross : 1/12/2011<br>terry : 1/6/2011<br>wwang : 7/18/2008<br>terry : 7/18/2008<br>mgross : 12/5/2006<br>carol : 8/1/2006<br>tkritzer : 7/15/2004<br>terry : 7/8/2004<br>terry : 3/18/2004<br>alopez : 2/17/2004<br>alopez : 1/30/2004<br>alopez : 1/8/2004<br>terry : 12/31/2003<br>mgross : 4/7/2003<br>terry : 4/1/2003<br>cwells : 6/12/2002<br>cwells : 6/7/2002<br>carol : 10/1/2001<br>carol : 10/1/2001<br>carol : 10/1/2001<br>psherman : 5/23/2000<br>carol : 11/9/1998<br>terry : 11/3/1998<br>mark : 9/26/1997<br>mark : 4/17/1996
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<strong>*</strong> 601205
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SIX HOMEOBOX 1; SIX1
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SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 1
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<strong><em>HGNC Approved Gene Symbol: SIX1</em></strong>
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Cytogenetic location: 14q23.1
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<strong>Gene-Phenotype Relationships</strong>
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14q23.1
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Branchiootic syndrome 3
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608389
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Autosomal dominant
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3
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Deafness, autosomal dominant 23
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605192
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The vertebrate SIX genes are homologs of the Drosophila 'sine oculis' (so) gene, which is expressed primarily in the developing visual system of the fly. Members of the SIX gene family encode proteins that are characterized by a divergent DNA-binding homeodomain and an upstream SIX domain, which may be involved both in determining DNA-binding specificity and in mediating protein-protein interactions. Genes in the SIX family have been shown to play roles in vertebrate and insect development or have been implicated in maintenance of the differentiated state of tissues (summary by Boucher et al., 2000). </p>
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<strong>Cloning and Expression</strong>
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<p>Boucher et al. (1996) cloned and sequenced a human SIX1 cDNA and showed by Northern blotting that it is expressed in adult skeletal muscle. The cDNA sequence and predicted protein sequence of the human and mouse genes are highly homologous, with 98% similarity over the entire predicted amino acid sequence. During mouse limb development at embryonic day 11.5, Six1 and Six2 are expressed distally over the posterior and anterior limb regions, respectively. However, by E14.5, expression of Six1 and Six2 is detected flanking the phalanges in domains corresponding to the anterior-posterior and dorsoventral axes, respectively. Six1 is also weakly expressed in skeletal muscles of the head and body during late development. </p><p>Ford et al. (1998) cloned the human SIX1 homeobox gene from late S phase mammary carcinoma cells and demonstrated that overexpression of SIX1 leads to an abrogation of the DNA damage-induced G2 cell cycle checkpoint. In addition, they found that overexpression of SIX1 occurs in a large percentage of mammary carcinomas and correlates strongly with metastatic breast disease. It appeared that studies of several cancer cell lines suggested that SIX1 may be overexpressed in multiple types of tumors. Thus, the studies linked SIX1 to the cell cycle as well as to tumor progression and provided further evidence that 'master regulators' involved in development may contribute to tumorigenicity. </p>
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<strong>Gene Function</strong>
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<p>Ridgeway and Skerjanc (2001) induced myogenesis in a mouse pluripotent stem cell line. Myogenesis was associated with increased expression of Pax3 (606597), followed by expression of the transcription factor Six1, its cofactor Eya2 (601654), and the transcription factor Mox1 (600147), prior to the induction of MyoD (159970) and myogenin (Myog; 159980) expression. </p><p>Yu et al. (2004) established highly and poorly metastatic rhabdomyosarcoma cell lines derived from a transgenic mouse model overexpressing Hgf/Sf (142409) and deficient for Ink4a/Arf (600160), in which skeletal muscle tumors reminiscent of those in embryonic rhabdomyosarcoma (268210) arise with very high penetrance and short latency (Sharp et al., 2002). Yu et al. (2004) then used cDNA microarray analysis of these cell lines to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies revealed that ezrin, encoded by Vil2 (123900), and Six1 have essential roles in determining the metastatic fate of rhabdomyosarcoma cells. VIL2 and SIX1 expression was enhanced in human rhabdomyosarcoma tissue, significantly correlating with clinical stage. </p><p>Buller et al. (2001) analyzed the functional importance of Eya (EYA1; 601653) domain missense mutations with respect to protein complex formation and cellular localization. Previously described point mutations did not alter protein localization; however, 3 mutations (glu330 to lys, 601653.0009; ser454 to pro, 601653.0012; and leu472 to arg, 601653.0013) disrupted interactions between Eya and Six1 in both yeast and mammalian cells. Binding to Six2 (604994) was not impeded. </p><p>Grifone et al. (2004) found that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 accumulated preferentially in the nuclei of fast-twitch muscles. Forced coexpression of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition to a fast-twitch fiber type, with activation of fast-twitch fiber-specific genes and a switch toward glycolytic metabolism. </p><p>SALL1 (602218) is a transcription factor that has a critical role in kidney development. Using gel retardation assays, reporter gene assays, and mutation analysis, Chai et al. (2006) showed that SIX1 directly bound the SALL1 promoter and induced SALL1 expression in a dose-dependent manner. </p><p>McCoy et al. (2009) found that misexpression of human SIX1 in adult mouse mammary gland epithelium induced tumors of multiple histologic subtypes in a dose-dependent manner. Most SIX1-induced tumors underwent an epithelial-to-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt (see 164820) signaling, including cyclin D1 (CCND1; 168461). SIX1 promoted a stem/progenitor cell phenotype in mouse mammary gland and in SIX1-dependent mammary tumors. Coexpression of SIX1 and cyclin D1 was detected in several human breast cancers and was predictive of poor prognosis. </p><p>Independently, Micalizzi et al. (2009) showed that SIX1 overexpression in human and mouse mammary epithelial cells induced EMT and metastasis, both of which were dependent on the ability of SIX1 to activate TGF-beta (TGFB1; 190180) signaling. Breast cancer patients whose tumors overexpressed SIX1 had a shortened time to relapse and metastasis and an overall decrease in survival. Similarly, overexpression of SIX1 correlated with adverse outcomes in a number of other cancers, including brain, cervical, prostate, colon, kidney, and liver. Micalizzi et al. (2009) concluded that SIX1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis. </p><p>Delgado-Olguin et al. (2012) found that conditional deletion of Ezh2 (601573) in mouse anterior heart field resulted in right cardiac hypertrophy and fibrosis after birth. Gene expression profiling of Ezh2-knockout hearts revealed derepression of Six1, with concomitant activation of Six1-dependent skeletal muscle-specific genes. Overexpression of Six1 in cultured neonatal mouse cardiomyocytes resulted in hypertrophy comparable to that induced by the hypertrophic agonist endothelin-1 (EDN1; 131240). Knockdown of Six1 in Ezh2-knockout hearts completely rescued the cardiac phenotype. </p><p>Liu et al. (2019) showed that the SIX homolog family transcription factors SIX1 and SIX2 (604994) are integral components of the noncanonical NF-kappa-B (see 164011) signaling cascade. The developmentally silenced SIX proteins were reactivated in differentiated macrophages by NIK (604655)-mediated suppression of the ubiquitin proteasome pathway. Consequently, SIX1 and SIX2 targeted a subset of inflammatory gene promoters and directly inhibited the trans-activation function of the transcription factors RELA (164014) and RELB (604758) in a negative feedback circuit. In support of a physiologically pivotal role for SIX proteins in host immunity, a human SIX1 transgene suppressed inflammation and promoted the recovery of mice from endotoxic shock. In addition, SIX1 and SIX2 protected RAS (see 190070)/P53 (191170)-driven non-small-cell lung carcinomas from inflammatory cell death induced by small molecule activators of the noncanonical NF-kappa-B pathway. </p>
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<strong>Evolution</strong>
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<p>Gallardo et al. (1999) performed phylogenetic analysis of SIX gene family members and presented a model for the origin and evolution of SIX gene clusters. </p>
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<strong>Mapping</strong>
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<p>Using a rodent/human somatic cell hybrid panel, Boucher et al. (1996) mapped the human SIX1 gene to chromosome 14. </p><p>Ruf et al. (2004) located the SIX1, SIX4 (606342), and SIX6 (606326) genes, which play a role in the EYA-SIX-PAX (see 167411) hierarchy of regulatory genes for the embryonic development of ear, kidney, and other organs, within a 33-Mb critical interval on chromosome 14q23. </p><p>Oliver et al. (1995) mapped the mouse Six1 gene to the central region of chromosome 12. </p>
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<strong>Molecular Genetics</strong>
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<p>Branchiootorenal syndrome (see 113650) is an autosomal dominant disorder characterized by hearing loss, branchial cleft fistulas or cysts, and renal dysplasia. Branchiootic syndrome (see 602588) is a related disorder without renal anomalies. Ruf et al. (2003) mapped a locus for the BOR/BO syndrome (BOS3; 608389) to chromosome 14q23. By direct sequencing of SIX1 exons, they identified 2 different mutations in the SIX1 gene in 3 kindreds with BOS3: tyr129 to cys (Y129C; 601205.0001) and arg110 to trp (R110W; 601205.0002). Both mutations are crucial for EYA1-SIX1 interaction, and the Y129C mutation, which is within the homeodomain region, is essential for specific SIX1-DNA binding. In a member of a fourth family, previously reported by Salam et al. (2000) with DFNA23 (605192), Ruf et al. (2004) identified a 3-bp deletion in the SIX1 gene (601205.0003). In addition to deafness, the patient had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure, suggesting that this family may have BOR/BO syndrome. </p><p>In 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome, Sanggaard et al. (2007) identified heterozygosity for a missense mutation in the SIX1 gene (601205.0004). </p><p>By direct sequencing of the SIX1 gene in an affected member of a Tunisian family with autosomal dominant hearing impairment and preauricular pits mapping to chromosome 14q23, Mosrati et al. (2011) identified a heterozygous missense mutation (E125K; 601205.0005) that segregated with the phenotype in family. </p>
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<p>Li et al. (2003) reported that Six1 is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya factors. Li et al. (2003) demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach (603803) from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog and in double knockouts for MyoD/Myf5 (159990) and Pax3/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland. </p><p>Bosman et al. (2009) reported 'catweasel' (cwe), an N-ethyl-N-nitrosourea-induced mutation that caused mild headbobbing in heterozygous cwe/+ mice. These mice lacked the eminentium cruciatum in the posterior crista and had extra inner hair cells in the organ of Corti. Bosman et al. (2009) identified cwe as a 411A-G transition in exon 1 of the Six1 gene, resulting in a glu135-to-gly (E135G) substitution of a highly conserved residue in the N-terminal part of the Six1 homeobox domain. The mutation did not alter Six1 expression, but it was predicted to destabilize binding of Six1 to DNA. Bosman et al. (2009) observed that the cwe/+ phenotype was less severe than the Six1 +/- phenotype. Homozygous cwe/cwe mice had a more severe phenotype than cwe/+ mice that resembled branchiootorenal syndrome, with extreme headshaking and circling behavior. Cwe/cwe animals appeared normal in most behavior tests, but they were deaf and lacked contact righting response and Preyer reflex. They also had severe vestibular abnormalities and defects in the inner and middle ear, lacked most sensory hair cells, and showed renal defects. Cwe/cwe embryos showed defects in sensory patch development as early as embryonic day 10.5. Bmp4 (112262), Jag1 (601920), and Sox2 (184429) expression was largely absent at early stages of sensory development, and NeuroD (see 601724) expression was reduced in developing vestibuloacoustic ganglion. Bosman et al. (2009) noted that htu/+ mice with a mutation in the Jag1 gene show a phenotype similar to cwe/+ mice. Experiments with cwe/+, htu/+, and double-heterozygous cwe/+ htu/+ mice suggested that Six1 acts upstream of Jag1 in the Notch signaling pathway. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 BRANCHIOOTIC SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SIX1, TYR129CYS
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<br />
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SNP: rs104894478,
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gnomAD: rs104894478,
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ClinVar: RCV000008806, RCV000413341, RCV000679883, RCV000763344, RCV002512918, RCV003390661, RCV004719033
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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 affected members of the kindred in which Ruf et al. (2003) mapped branchiootic syndrome-3 (BOS3; 608389) to 14q, Ruf et al. (2004) identified heterozygosity for a 386A-G transition in exon 1 of the SIX1 gene, resulting in a tyr129-to-cys (Y129C) mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 BRANCHIOOTIC SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SIX1, ARG110TRP
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<br />
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SNP: rs80356459,
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ClinVar: RCV000008807, RCV002262561, RCV002512919
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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 affected members of 2 families with branchiootic syndrome-3 (BOS3; 608389), Ruf et al. (2004) identified heterozygosity for a 328C-T transition in exon 1 of the SIX1 gene, resulting in an arg110-to-trp (R110W) mutation. Branchial and otic defects were present in affected members of both families. </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>.0003 DEAFNESS, AUTOSOMAL DOMINANT 23</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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SIX1, 3-BP DEL, 397GGA
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<br />
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SNP: rs80356460,
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ClinVar: RCV000008808, RCV000020636, RCV002512920, RCV003162220
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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 member of a family previously reported by Salam et al. (2000) with DFNA23 (605192), Ruf et al. (2004) identified heterozygosity for a 3-bp deletion (397delGGA) in the SIX1 gene, resulting in the deletion of glutamic acid at position 133. In addition to deafness, the patient had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure, suggesting that this family may have BOR/BO syndrome. </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>.0004 BRANCHIOOTIC SYNDROME 3</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SIX1, TRP122ARG
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<br />
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|
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SNP: rs121909770,
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ClinVar: RCV000008809
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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 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome-3 (BOS3; 608389), Sanggaard et al. (2007) identified heterozygosity for a 364T-A transversion in exon 1 of the SIX1 gene, resulting in a trp122-to-arg (W122R) substitution at a conserved residue. The mutation was not found in unaffected family members or in 140 control chromosomes. </p>
|
|
</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>.0005 DEAFNESS, AUTOSOMAL DOMINANT 23</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
SIX1, GLU125LYS
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|
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<br />
|
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|
|
SNP: rs797044960,
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|
|
|
|
ClinVar: RCV000190433, RCV001852527, RCV002478668
|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>By direct sequencing of the SIX1 gene in an affected member of a Tunisian family with autosomal dominant hearing impairment and preauricular pits mapping to 14q23, Mosrati et al. (2011) identified a heterozygous c.373G-A transition, predicted to result in a glu125-to-lys (E125K) substitution at a conserved residue. Segregation of the variant with the phenotype was confirmed by PCR restriction fragment length polymorphism. The glu125 residue is located in the N-terminal arm and is likely to affect DNA binding. </p>
|
|
</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>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Bosman, E. A., Quint, E., Fuchs, H., Hrabe de Angelis, M., Steel, K. P.
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<strong>Catweasel mice: a novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.</strong>
|
|
Dev. Biol. 328: 285-296, 2009.
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[PubMed: 19389353]
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[Full Text: https://doi.org/10.1016/j.ydbio.2009.01.030]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Boucher, C. A., Carey, N., Edwards, Y. H., Siciliano, M. J., Johnson, K. J.
|
|
<strong>Cloning of the human SIX1 gene and its assignment to chromosome 14.</strong>
|
|
Genomics 33: 140-142, 1996.
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[PubMed: 8617500]
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[Full Text: https://doi.org/10.1006/geno.1996.0172]
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<li>
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<p class="mim-text-font">
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|
Boucher, C. A., Winchester, C. L., Hamilton, G. M., Winter, A. D., Johnson, K. J., Bailey, M. E. S.
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<strong>Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2.</strong>
|
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Gene 247: 145-151, 2000.
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[PubMed: 10773454]
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[Full Text: https://doi.org/10.1016/s0378-1119(00)00105-0]
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<li>
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<p class="mim-text-font">
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Buller, C., Xu, X., Marquis, V., Schwanke, R., Xu, P.-X.
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<strong>Molecular effects of Eya1 domain mutations causing organ defects in BOR syndrome.</strong>
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Hum. Molec. Genet. 10: 2775-2781, 2001.
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[PubMed: 11734542]
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[Full Text: https://doi.org/10.1093/hmg/10.24.2775]
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<li>
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<p class="mim-text-font">
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Chai, L., Yang, J., Di, C., Cui, W., Kawakami, K., Lai, R., Ma, Y.
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<strong>Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development.</strong>
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J. Biol. Chem. 281: 18918-18926, 2006.
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[PubMed: 16670092]
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[Full Text: https://doi.org/10.1074/jbc.M600180200]
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<li>
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<p class="mim-text-font">
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Delgado-Olguin, P., Huang, Y., Li, X., Christodoulou, D., Seidman, C. E., Seidman, J. G., Tarakhovsky, A., Bruneau, B. G.
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<strong>Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.</strong>
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Nature Genet. 44: 343-347, 2012.
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[PubMed: 22267199]
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[Full Text: https://doi.org/10.1038/ng.1068]
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</p>
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<li>
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<p class="mim-text-font">
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Ford, H. L., Kabingu, E. N., Bump, E. A., Mutter, G. L., Pardee, A. B.
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<strong>Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.</strong>
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Proc. Nat. Acad. Sci. 95: 12608-12613, 1998.
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[PubMed: 9770533]
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[Full Text: https://doi.org/10.1073/pnas.95.21.12608]
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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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Gallardo, M. E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M. J., Brunner, H. G., Bovolenta, P., Rodriguez de Cordoba, S.
|
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<strong>Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies.</strong>
|
|
Genomics 61: 82-91, 1999.
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[PubMed: 10512683]
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[Full Text: https://doi.org/10.1006/geno.1999.5916]
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</p>
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<li>
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<p class="mim-text-font">
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Grifone, R., Laclef, C., Spitz, F., Lopez, S., Demignon, J., Guidotti, J.-E., Kawakami, K., Xu, P.-X., Kelly, R., Petrof, B. J., Daegelen, D., Concordet, J.-P., Maire, P.
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<strong>Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.</strong>
|
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Molec. Cell. Biol. 24: 6253-6267, 2004.
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[PubMed: 15226428]
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[Full Text: https://doi.org/10.1128/MCB.24.14.6253-6267.2004]
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<li>
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<p class="mim-text-font">
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Li, X., Ohgi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., Rosenfeld, M. G.
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<strong>Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.</strong>
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Nature 426: 247-254, 2003. Note: Erratum: Nature 427: 265 only, 2004.
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[PubMed: 14628042]
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[Full Text: https://doi.org/10.1038/nature02083]
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</p>
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<li>
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<p class="mim-text-font">
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Liu, Z., Mar, K. B., Hanners, N. W., Perelman, S. S., Kanchwala, M., Xing, C., Schoggins, J. W., Alto, N. M.
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<strong>A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-kappa-B.</strong>
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Nature 568: 249-253, 2019.
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[PubMed: 30894749]
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[Full Text: https://doi.org/10.1038/s41586-019-1041-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
McCoy, E. L., Iwanaga, R., Jedlicka, P., Abbey, N.-S., Chodosh, L. A., Heichman, K. A., Welm, A. L., Ford, H. L.
|
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<strong>Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.</strong>
|
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J. Clin. Invest. 119: 2663-2677, 2009.
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|
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[PubMed: 19726883]
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[Full Text: https://doi.org/10.1172/JCI37691]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Micalizzi, D. S., Christensen, K. L., Jedlicka, P., Coletta, R. D., Baron, A. E., Harrell, J. C., Horwitz, K. B., Billheimer, D., Heichman, K. A., Welm, A. L., Schiemann, W. P., Ford, H. L.
|
|
<strong>The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.</strong>
|
|
J. Clin. Invest. 119: 2678-2690, 2009.
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|
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[PubMed: 19726885]
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|
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[Full Text: https://doi.org/10.1172/JCI37815]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Mosrati, M. A., Hammami, B., Rebeh, I. B., Ayadi, L., Dhouib, L., Ben Mahfoudh, K., Hakim, B., Charfeddine, I., Mnif, J., Ghorbel, A., Masmoudi, S.
|
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<strong>A novel dominant mutation in SIX1, affecting a highly conserved residue, result (sic) in only auditory defects in humans.</strong>
|
|
Europ. J. Med. Genet. 54: e484-e488, 2011. Note: Electronic Article.
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[PubMed: 21700001]
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[Full Text: https://doi.org/10.1016/j.ejmg.2011.06.001]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Oliver, G., Wehr, R., Jenkins, N. A., Copeland, N. G., Cheyette, B. N. R., Hartenstein, V., Zipursky, S. L., Gruss, P.
|
|
<strong>Homeobox genes and connective tissue patterning.</strong>
|
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Development 121: 693-705, 1995.
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[PubMed: 7720577]
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[Full Text: https://doi.org/10.1242/dev.121.3.693]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ridgeway, A. G., Skerjanc, I. S.
|
|
<strong>Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2.</strong>
|
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J. Biol. Chem. 276: 19033-19039, 2001.
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[PubMed: 11262400]
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[Full Text: https://doi.org/10.1074/jbc.M011491200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ruf, R. G., Berkman, J., Wolf, M. T. F., Nurnberg, P., Gattas, M., Ruf, E.-M., Hyland, V., Kromberg, J., Glass, I., Macmillan, J., Otto, E., Nurnberg, G., Lucke, B., Hennies, H. C., Hildebrandt, F.
|
|
<strong>A gene locus for branchio-otic syndrome maps to chromosome 14q21.3-q24.3.</strong>
|
|
J. Med. Genet. 40: 515-519, 2003.
|
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|
|
[PubMed: 12843324]
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|
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[Full Text: https://doi.org/10.1136/jmg.40.7.515]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others.
|
|
<strong>SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 8090-8095, 2004.
|
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|
|
[PubMed: 15141091]
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[Full Text: https://doi.org/10.1073/pnas.0308475101]
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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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Salam, A. A., Hafner, F. M., Linder, T. E., Spillmann, T., Schinzel, A. A., Leal, S. M.
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<strong>A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred.</strong>
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Am. J. Hum. Genet. 66: 1984-1988, 2000.
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Sanggaard, K. M., Rendtorff, N. D., Kjaer, K. W., Eiberg, H., Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K. O., Lage, K., Tranebjaerg, L.
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<strong>Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses.</strong>
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Europ. J. Hum. Genet. 15: 1121-1131, 2007.
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Sharp, R., Recio, J. A., Jhappan, C., Otsuka, T., Liu, S., Yu, Y., Liu, W., Anver, M., Navid, F., Helman, L. J., DePinho, R. A., Merlino, G.
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<strong>Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.</strong>
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Nature Med. 8: 1276-1280, 2002. Note: Erratum: Nature Med. 9: 146 only, 2003.
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[PubMed: 12368906]
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[Full Text: https://doi.org/10.1038/nm787]
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Yu, Y., Khan, J., Khanna, C., Helman, L., Meltzer, P. S., Merlino, G.
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<strong>Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.</strong>
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Nature Med. 10: 175-181, 2004.
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[PubMed: 14704789]
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[Full Text: https://doi.org/10.1038/nm966]
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Ada Hamosh - updated : 08/20/2019<br>Patricia A. Hartz - updated : 8/24/2015<br>Joanna S. Amberger - updated : 8/21/2015<br>Patricia A. Hartz - updated : 3/19/2012<br>Patricia A. Hartz - updated : 1/6/2011<br>Marla J. F. O'Neill - updated : 7/18/2008<br>Patricia A. Hartz - updated : 12/5/2006<br>Victor A. McKusick - updated : 7/8/2004<br>Ada Hamosh - updated : 1/30/2004<br>Ada Hamosh - updated : 12/31/2003<br>Patricia A. Hartz - updated : 4/1/2003<br>George E. Tiller - updated : 6/7/2002<br>Patti M. Sherman - updated : 5/23/2000<br>Victor A. McKusick - updated : 11/3/1998
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Victor A. McKusick : 4/16/1996
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