3242 lines
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Entry
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- *600963 - SIX HOMEOBOX 5; SIX5
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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">*600963</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600963">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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<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 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 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=ENSG00000177045;t=ENST00000317578" 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=147912" 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=600963" 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=ENSG00000177045;t=ENST00000317578" 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_175875" 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_175875" 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=600963" 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=09024&isoform_id=09024_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/SIX5" 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/21619989,119577783,150421671,1519314463" 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/Q8N196" 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=147912" 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=ENSG00000177045;t=ENST00000317578" 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=SIX5" 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=SIX5" 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+147912" 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/SIX5" 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:147912" 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/147912" 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=chr19&hgg_gene=ENST00000317578.7&hgg_start=45764785&hgg_end=45769252&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/genes/HGNC:10891" 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/six5" 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=600963[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=600963[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/SIX5/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/ENSG00000177045" 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=SIX5" 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=SIX5" 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=SIX5" 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=SIX5&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/PA35791" 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:10891" 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/FBgn0027364.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:106220" 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/SIX5#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:106220" 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/147912/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=147912" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006775;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-010201-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=SIX5&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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600963
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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 5; SIX5
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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">
|
|
SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 5<br />
|
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DM LOCUS-ASSOCIATED HOMEODOMAIN PROTEIN; DMAHP
|
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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=SIX5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SIX5</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/19/832?start=-3&limit=10&highlight=832">19q13.32</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:45764785-45769252&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'})">19:45,764,785-45,769,252</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">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/19/832?start=-3&limit=10&highlight=832">
|
|
19q13.32
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Branchiootorenal syndrome 2
|
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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/610896"> 610896 </a>
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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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</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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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600963" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600963" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<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="#2" 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="#1" class="mim-tip-reference" title="Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J. <strong>A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.</strong> Hum. Molec. Genet. 4: 1919-1925, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595416</a>] [<a href="https://doi.org/10.1093/hmg/4.10.1919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595416">Boucher et al. (1995)</a> identified SIX5 as a homeodomain protein gene downstream (centromeric) of the (CTG)n repeat in the DMPK gene (<a href="/entry/160900">160900</a>). RT-PCR analysis showed that the SIX5 gene, which they called DMAHP, is expressed in a number of human tissues, including skeletal muscle, heart, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Heath, S. K., Carne, S., Hoyle, C., Johnson, K. J., Wells, D. J. <strong>Characterisation of expression of mDMAHP, a homeodomain-encoding gene at the murine DM locus.</strong> Hum. Molec. Genet. 6: 651-657, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158137</a>] [<a href="https://doi.org/10.1093/hmg/6.5.651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158137">Heath et al. (1997)</a> used 2 different strategies to examine expression of the murine homolog of the DMAHP gene. The first approach, RT-PCR, detected spliced transcripts in a wide range of embryonic and adult tissues, in a pattern overlapping substantially with the expression of mouse DMPK. A second approach, the generation of transgenic mice expressing a lacZ reporter gene from a 4.3-kb DMAHP promoter fragment, also demonstrated expression in a range of tissues with potential links to the phenotype in myotonic dystrophy. They concluded that murine DMAHP has a similar pattern of expression to human DMAHP and that the mouse can serve as a useful model for functional studies of this gene, although species differences, such as the reduced CpG island (1.8 kb compared with 3.5 kb), must be kept in mind. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9158137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Myotonic dystrophy (<a href="/entry/160900">160900</a>) is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting with myotonia, cataracts, heart block, gonadal atrophy, insulin resistance, and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene, though the pathophysiologic mechanism for multisystem degeneration in DM had yet to be defined. Among the triplet repeat expansion disorders, myotonic dystrophy is distinguished by the extended length of the repeat tract (5 to 13 kb in postmortem tissue) and its location in the 3-prime untranslated region of the DMPK gene. <a href="#13" class="mim-tip-reference" title="Thornton, C. A., Wymer, J. P., Simmons, Z., McClain, C., Moxley, R. T., III. <strong>Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.</strong> Nature Genet. 16: 407-409, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241283</a>] [<a href="https://doi.org/10.1038/ng0897-407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241283">Thornton et al. (1997)</a> noted that, in contrast to the profound muscle wasting that characterizes advanced myotonic dystrophy, only minor histopathologic abnormalities were found in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. <a href="#9" class="mim-tip-reference" title="Otten, A. D., Tapscott, S. J. <strong>Triple-repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.</strong> Proc. Nat. Acad. Sci. 92: 5465-5469, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7777532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7777532</a>] [<a href="https://doi.org/10.1073/pnas.92.12.5465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7777532">Otten and Tapscott (1995)</a> demonstrated that a DNase I (<a href="/entry/300081">300081</a>)-hypersensitive site located adjacent to the repeats on the wildtype allele is eliminated by repeat expansion, suggesting that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. <a href="#6" class="mim-tip-reference" title="Klesert, T. R., Otten, A. D., Bird, T. D., Tapscott, S. J. <strong>Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.</strong> Nature Genet. 16: 402-406, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241282</a>] [<a href="https://doi.org/10.1038/ng0897-402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241282">Klesert et al. (1997)</a> reported that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Analysis of DMAHP expression in cells of myotonic dystrophy patients with loss of the hypersensitive site revealed a 2- to 4-fold reduction in the steady-state DMAHP transcript levels relative to wildtype controls. Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wildtype allele. Along the same line, <a href="#13" class="mim-tip-reference" title="Thornton, C. A., Wymer, J. P., Simmons, Z., McClain, C., Moxley, R. T., III. <strong>Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.</strong> Nature Genet. 16: 407-409, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241283</a>] [<a href="https://doi.org/10.1038/ng0897-407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9241283">Thornton et al. (1997)</a> showed that DMAHP expression in myoblasts, muscle, and myocardium was reduced by the DM mutation in cis, and the magnitude of this effect depended on the extent of the CTG repeat expansion. These observations supported the hypothesis that DMAHP participates in the pathophysiology of DM. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9241283+7777532+9241282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Since the DM-associated (CTG)n repeat is located in the promoter region of SIX5, immediately downstream of DMPK, <a href="#14" class="mim-tip-reference" title="Winchester, C. L., Ferrier, R. K., Sermoni, A., Clark, B. J., Johnson, K. J. <strong>Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.</strong> Hum. Molec. Genet. 8: 481-492, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949207</a>] [<a href="https://doi.org/10.1093/hmg/8.3.481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949207">Winchester et al. (1999)</a> hypothesized that dysfunction of this gene, which is homologous to the Drosophila eye development gene 'sine oculis,' is primarily responsible for the ophthalmic features of DM. The multicolored iridescent cataract is the most prominent feature of the eye pathology in DM. It is often the first and in some cases the only sign of the disease, occurring at a younger age than is expected for senile cataracts, and occurring in persons who show no muscle symptoms or who carry a premutation (CTG)n repeat allele. In an analysis of the expression of DMPK and SIX5 in normal human fetal and adult eyes, <a href="#14" class="mim-tip-reference" title="Winchester, C. L., Ferrier, R. K., Sermoni, A., Clark, B. J., Johnson, K. J. <strong>Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.</strong> Hum. Molec. Genet. 8: 481-492, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949207</a>] [<a href="https://doi.org/10.1093/hmg/8.3.481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949207">Winchester et al. (1999)</a> found SIX5 transcripts in the adult corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina, and the sclera. SIX5 expression was not detected in fetal eyes. They also reported a restricted but partially overlapping expression pattern for DMPK transcripts and DMPK protein in normal fetal and adult eyes. <a href="#14" class="mim-tip-reference" title="Winchester, C. L., Ferrier, R. K., Sermoni, A., Clark, B. J., Johnson, K. J. <strong>Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.</strong> Hum. Molec. Genet. 8: 481-492, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949207</a>] [<a href="https://doi.org/10.1093/hmg/8.3.481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949207">Winchester et al. (1999)</a> concluded that the expression of SIX5 and not DMPK in the adult lens indicated a role for SIX5 dysfunction in the development of adult-onset cataracts, the most frequently occurring eye phenotype in DM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#1" class="mim-tip-reference" title="Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J. <strong>A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.</strong> Hum. Molec. Genet. 4: 1919-1925, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595416</a>] [<a href="https://doi.org/10.1093/hmg/4.10.1919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595416">Boucher et al. (1995)</a> identified the SIX5 gene in chromosome 19q13.3, centromeric to the DMPK gene (<a href="/entry/605377">605377</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 (BOR2; <a href="/entry/610896">610896</a>) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in the EYA1 gene (<a href="/entry/601653">601653</a>) were identified as a cause of the BOR syndrome. A member of the SIX family of proteins, unc-39 (SIX5), was found to interact directly with eya-1 in Caenorhabditis elegans as identified by high-throughput, yeast 2-hybrid analysis (<a href="#8" class="mim-tip-reference" title="Li, S., Armstrong, C. M., Bertin, N., Ge, H., Milstein, S., Boxem, M., Vadalain, P.-O., Han, J.-D. J., Chesneau, A., Hao, T., Goldberg, D. S., Li, N., and 36 others. <strong>A map of the interactome network of the metazoan C. elegans.</strong> Science 303: 540-543, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14704431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14704431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14704431[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1091403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14704431">Li et al., 2004</a>). <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. They therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in 5 individuals with BOR2. Functional analyses of these mutations demonstrated that 2 mutations (<a href="#0001">600963.0001</a>, <a href="#0004">600963.0004</a>) affected EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14704431+17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1 of the patients reported by <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> as carrying a mutation in the SIX5 gene (T552M; <a href="#0004">600963.0004</a>), <a href="#7" class="mim-tip-reference" title="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a> identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused <a href="#7" class="mim-tip-reference" title="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a> to reconsider the role of SIX5 in branchiootorenal syndrome etiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21280147+17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Klesert, T. R., Cho, D. H., Clark, J. I., Maylie, J., Adelman, J., Snider, L., Yuen, E. C., Soriano, P., Tapscott, S. J. <strong>Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.</strong> Nature Genet. 25: 105-109, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802667</a>] [<a href="https://doi.org/10.1038/75490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802667">Klesert et al. (2000)</a> replaced the first exon of Six5 with a beta-galactosidase reporter gene. Histochemical detection of beta-galactosidase activity demonstrated expression as early as 8.5 days postcoitum in the anterior neural folds. Between 10.5 and 15.5 days postcoitum, there was low expression in smooth muscle of stomach, esophagus, and urogenital sinus, and in skeletal muscle of the tongue, as well as scattered expression in the myotome and developing limb muscle. A higher level of expression was seen in the sclerotome, meninges, adrenal gland, and cartilaginous areas of developing bones and trachea. In the eye, expression was evident in the retina, the cornea, the vasculature on the posterior surface of the lens, and faintly in the lens-fiber layer. There was no reliable expression detected in the adult mouse. Disruption of Six5 function did not affect viability or fertility. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. <a href="#5" class="mim-tip-reference" title="Klesert, T. R., Cho, D. H., Clark, J. I., Maylie, J., Adelman, J., Snider, L., Yuen, E. C., Soriano, P., Tapscott, S. J. <strong>Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.</strong> Nature Genet. 25: 105-109, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802667</a>] [<a href="https://doi.org/10.1038/75490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802667">Klesert et al. (2000)</a> concluded that Six5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sarkar, P. S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J. T., Reddy, S. <strong>Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.</strong> Nature Genet. 25: 110-114, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802668</a>] [<a href="https://doi.org/10.1038/75500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802668">Sarkar et al. (2000)</a> also studied Six5 expression in mouse. By in situ hybridization, they detected Six5 expression in the adult corneal epithelium and endothelium, inner and outer epithelium of the ciliary body, anterior lens epithelium, ganglion cells, cells of the inner nuclear layer, and photoreceptor cells of the retina. <a href="#10" class="mim-tip-reference" title="Sarkar, P. S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J. T., Reddy, S. <strong>Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.</strong> Nature Genet. 25: 110-114, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802668</a>] [<a href="https://doi.org/10.1038/75500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802668">Sarkar et al. (2000)</a> deleted the entire Six5 gene and replaced it with a neo cassette. They found that the rate and severity of cataract formation was inversely related to Six5 dosage and was temporally progressive. Six5 +/- and Six5 -/- mice showed increased steady-state levels of the sodium-potassium-ATPase alpha-1 subunit (<a href="/entry/182310">182310</a>) and decreased Dm15 mRNA levels. <a href="#10" class="mim-tip-reference" title="Sarkar, P. S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J. T., Reddy, S. <strong>Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.</strong> Nature Genet. 25: 110-114, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802668</a>] [<a href="https://doi.org/10.1038/75500" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10802668">Sarkar et al. (2000)</a> suggested that altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrated that decreased Six5 transcription is important in the etiology of DM. The authors concluded that their data supported the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Sato, S., Nakamura, M., Cho, D. H., Tapscott, S. J., Ozaki, H., Kawakami, K. <strong>Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1.</strong> Hum. Molec. Genet. 11: 1045-1058, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978764</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978764">Sato et al. (2002)</a> overexpressed a constitutively active form of Six5 in murine P19 embryonal carcinoma cells. Using expression profiling in cDNA arrays, they identified 21 potential target genes whose expression level increased by the treatment. Genes expressed in the somites, skeletal muscles, brain, and meninges comprised the majority, suggesting a role for Six5 in the development and function of mesodermal tissues and brain. One of these genes, Igfbp5 (<a href="/entry/146734">146734</a>), was also decreased in Six5-deficient mouse fibroblasts, and the response of human IGFBP5 to MyoD (<a href="/entry/159970">159970</a>)-induced muscle conversion was altered in cells of DM patients. The authors concluded that Six5 is an activator that directs Igfbp5 expression, and hypothesized that reduced SIX5 expression in DM contributes to the DM phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978764" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The CTG expansion causing DM results in transcriptional silencing of the flanking SIX5 allele. <a href="#11" class="mim-tip-reference" title="Sarkar, P. S., Paul, S., Han, J., Reddy, S. <strong>Six5 is required for spermatogenic cell survival and spermiogenesis.</strong> Hum. Molec. Genet. 13: 1421-1431, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15163633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15163633</a>] [<a href="https://doi.org/10.1093/hmg/ddh161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15163633">Sarkar et al. (2004)</a> generated Six5 knockout and heterozygous mice by targeted disruption and demonstrated a strict requirement of Six5 for both spermatogenic cell survival and spermiogenesis. Leydig cell hyperproliferation and increased intratesticular testosterone levels were observed in the Six5 -/- mice. Although increased FSH (see <a href="/entry/136530">136530</a>) levels were observed in the Six5 +/- and Six5 -/- mice, serum testosterone levels and intratesticular inhibin alpha (INHA; <a href="/entry/147380">147380</a>) and inhibin beta-B (INHBB; <a href="/entry/147390">147390</a>) levels were not altered in the Six5 mutant animals when compared with controls. Steady-state c-Kit (<a href="/entry/164920">164920</a>) levels were reduced in the Six5 -/- testis. The authors concluded that decreased c-Kit levels could contribute to the elevated spermatogenic cell apoptosis and Leydig cell hyperproliferation in the Six5 -/- mice. They hypothesized that the reduced SIX5 levels may contribute to the male reproductive defects in DM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15163633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with branchiootorenal syndrome (BOR2; <a href="/entry/610896">610896</a>) manifesting bilateral dysplastic kidneys and preauricular tag on the right but no hearing loss, <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> identified a heterozygous 472G-A transition in the SIX5 gene that resulted in an ala158-to-thr (A158T) amino acid substitution. Using yeast 2-hybrid analysis and luciferase assays, <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> showed that this mutation reduced EYA1-SIX5 binding and the ability of the EYA1-SIX5 complex to activate gene transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000009130 OR RCV001723554 OR RCV004752693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009130, RCV001723554, RCV004752693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009130...</a>
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<p>In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; <a href="/entry/610896">610896</a>) who had bilateral dysplastic kidneys and reduced renal function, bilateral hearing loss and cervical fistulae, and right-sided hemifacial microsomia, preauricular sinus, and pinna malformation, <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> identified a heterozygous 886G-A transition in the SIX5 gene that resulted in an ala296-to-thr (A296T) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 BRANCHIOOTORENAL SYNDROME 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80356463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356463;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/rs80356463?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=rs80356463" 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=rs80356463" 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=RCV000009131" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009131" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009131</a>
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<p>In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; <a href="/entry/610896">610896</a>), <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> found a heterozygous 1093G-A transition in the SIX5 gene that resulted in a gly365-to-arg (G365R) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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SIX5, THR552MET
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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> rs80356464 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356464;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/rs80356464?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=rs80356464" 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=rs80356464" 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=RCV000009132 OR RCV001851753" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009132, RCV001851753" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009132...</a>
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<p>This variant, formerly titled BRANCHIOOTORENAL SYNDROME 2, has been reclassified based on the findings of <a href="#7" class="mim-tip-reference" title="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21280147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with the BOR syndrome (BOR2; <a href="/entry/610896">610896</a>), <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> found heterozygosity for the same missense mutation in the SIX5 gene, a 1655C-T transition that resulted in a thr552-to-met (T552M) substitution. One patient had no hearing loss but had bilateral hypoplastic kidneys and cervical fistulae; the second patient had agenesis of the left kidney and hypoplasia of the right kidney, bilateral cervical fistulae, and bilateral hearing loss. Using yeast 2-hybrid analysis and luciferase assays, <a href="#4" class="mim-tip-reference" title="Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F. <strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong> Am. J. Hum. Genet. 80: 800-804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/513322" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17357085">Hoskins et al. (2007)</a> showed that this mutation reduced EYA1-SIX5 binding and the ability of the EYA1-SIX5 complex to activate gene transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L. <strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong> Hum. Mutat. 32: 183-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>] [<a href="https://doi.org/10.1002/humu.21402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21280147">Krug et al. (2011)</a> demonstrated that one of the patients carrying the T552M mutation had a 3-exon deletion in the EYA1 gene (<a href="/entry/601653">601653</a>). This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This patient had an affected twin brother and an affected father; both the T552M SIX5 and the 3-exon deletion in EYA1 were found in these family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21280147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Boucher1995" class="mim-anchor"></a>
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Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J.
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[<a href="https://doi.org/10.1093/hmg/4.10.1919" target="_blank">Full Text</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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[<a href="https://doi.org/10.1016/s0378-1119(00)00105-0" target="_blank">Full Text</a>]
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Heath, S. K., Carne, S., Hoyle, C., Johnson, K. J., Wells, D. J.
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<strong>Characterisation of expression of mDMAHP, a homeodomain-encoding gene at the murine DM locus.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9158137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F.
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<strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong>
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Am. J. Hum. Genet. 80: 800-804, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17357085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17357085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17357085[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=17357085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.</strong>
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Nature Genet. 25: 105-109, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802667</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802667" 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/10.1038/75490" target="_blank">Full Text</a>]
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</p>
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<a id="6" class="mim-anchor"></a>
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<a id="Klesert1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Klesert, T. R., Otten, A. D., Bird, T. D., Tapscott, S. J.
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<strong>Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.</strong>
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Nature Genet. 16: 402-406, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241282" 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/ng0897-402" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Krug2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Krug, P., Moriniere, V., Marlin, S., Koubi, V., Gabriel, H. D., Colin, E., Bonneau, D., Salomon, R., Antignac, C., Heidet, L.
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<strong>Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations.</strong>
|
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Hum. Mutat. 32: 183-190, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21280147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21280147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21280147" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21402" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Li2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Li, S., Armstrong, C. M., Bertin, N., Ge, H., Milstein, S., Boxem, M., Vadalain, P.-O., Han, J.-D. J., Chesneau, A., Hao, T., Goldberg, D. S., Li, N., and 36 others.
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<strong>A map of the interactome network of the metazoan C. elegans.</strong>
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Science 303: 540-543, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14704431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14704431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14704431[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=14704431" 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/10.1126/science.1091403" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Otten1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Otten, A. D., Tapscott, S. J.
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<strong>Triple-repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.</strong>
|
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Proc. Nat. Acad. Sci. 92: 5465-5469, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7777532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7777532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7777532" 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.92.12.5465" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Sarkar2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sarkar, P. S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J. T., Reddy, S.
|
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<strong>Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.</strong>
|
|
Nature Genet. 25: 110-114, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10802668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10802668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10802668" 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/10.1038/75500" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Sarkar2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sarkar, P. S., Paul, S., Han, J., Reddy, S.
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<strong>Six5 is required for spermatogenic cell survival and spermiogenesis.</strong>
|
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Hum. Molec. Genet. 13: 1421-1431, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15163633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15163633</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15163633" 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/ddh161" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Sato2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sato, S., Nakamura, M., Cho, D. H., Tapscott, S. J., Ozaki, H., Kawakami, K.
|
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<strong>Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1.</strong>
|
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Hum. Molec. Genet. 11: 1045-1058, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978764</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978764" 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/11.9.1045" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Thornton1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thornton, C. A., Wymer, J. P., Simmons, Z., McClain, C., Moxley, R. T., III.
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<strong>Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.</strong>
|
|
Nature Genet. 16: 407-409, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9241283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9241283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241283" 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/ng0897-407" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Winchester1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winchester, C. L., Ferrier, R. K., Sermoni, A., Clark, B. J., Johnson, K. J.
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<strong>Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.</strong>
|
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Hum. Molec. Genet. 8: 481-492, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.3.481" target="_blank">Full Text</a>]
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/5/2014
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick - updated : 3/27/2007<br>George E. Tiller - updated : 9/21/2006<br>George E. Tiller - updated : 12/13/2002<br>Ada Hamosh - updated : 4/27/2000<br>Victor A. McKusick - updated : 3/19/1999<br>Victor A. McKusick - updated : 8/1/1997<br>Victor A. McKusick - updated : 6/23/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/4/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/15/2019
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/14/2018<br>carol : 09/13/2016<br>carol : 04/10/2015<br>alopez : 12/5/2014<br>terry : 9/20/2007<br>ckniffin : 6/8/2007<br>alopez : 3/29/2007<br>terry : 3/27/2007<br>alopez : 9/21/2006<br>terry : 3/18/2004<br>cwells : 12/13/2002<br>alopez : 4/29/2000<br>terry : 4/27/2000<br>mgross : 4/8/1999<br>mgross : 3/29/1999<br>mgross : 3/26/1999<br>terry : 3/19/1999<br>carol : 1/13/1999<br>dkim : 12/16/1998<br>terry : 8/5/1997<br>alopez : 8/4/1997<br>terry : 8/1/1997<br>terry : 6/23/1997<br>terry : 6/18/1997<br>mark : 2/28/1996<br>terry : 2/21/1996<br>mark : 1/5/1996<br>mark : 1/4/1996
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600963
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SIX HOMEOBOX 5; SIX5
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
SINE OCULIS HOMEOBOX, DROSOPHILA, HOMOLOG OF, 5<br />
|
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DM LOCUS-ASSOCIATED HOMEODOMAIN PROTEIN; DMAHP
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: SIX5</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 19q13.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:45,764,785-45,769,252 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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|
Location
|
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</th>
|
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<th>
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|
Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
|
</th>
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
19q13.32
|
|
</span>
|
|
</td>
|
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|
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|
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<td>
|
|
<span class="mim-font">
|
|
Branchiootorenal syndrome 2
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
610896
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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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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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</h4>
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<span class="mim-text-font">
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<p>Boucher et al. (1995) identified SIX5 as a homeodomain protein gene downstream (centromeric) of the (CTG)n repeat in the DMPK gene (160900). RT-PCR analysis showed that the SIX5 gene, which they called DMAHP, is expressed in a number of human tissues, including skeletal muscle, heart, and brain. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p>Heath et al. (1997) used 2 different strategies to examine expression of the murine homolog of the DMAHP gene. The first approach, RT-PCR, detected spliced transcripts in a wide range of embryonic and adult tissues, in a pattern overlapping substantially with the expression of mouse DMPK. A second approach, the generation of transgenic mice expressing a lacZ reporter gene from a 4.3-kb DMAHP promoter fragment, also demonstrated expression in a range of tissues with potential links to the phenotype in myotonic dystrophy. They concluded that murine DMAHP has a similar pattern of expression to human DMAHP and that the mouse can serve as a useful model for functional studies of this gene, although species differences, such as the reduced CpG island (1.8 kb compared with 3.5 kb), must be kept in mind. </p><p>Myotonic dystrophy (160900) is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting with myotonia, cataracts, heart block, gonadal atrophy, insulin resistance, and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene, though the pathophysiologic mechanism for multisystem degeneration in DM had yet to be defined. Among the triplet repeat expansion disorders, myotonic dystrophy is distinguished by the extended length of the repeat tract (5 to 13 kb in postmortem tissue) and its location in the 3-prime untranslated region of the DMPK gene. Thornton et al. (1997) noted that, in contrast to the profound muscle wasting that characterizes advanced myotonic dystrophy, only minor histopathologic abnormalities were found in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. Otten and Tapscott (1995) demonstrated that a DNase I (300081)-hypersensitive site located adjacent to the repeats on the wildtype allele is eliminated by repeat expansion, suggesting that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. Klesert et al. (1997) reported that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. Analysis of DMAHP expression in cells of myotonic dystrophy patients with loss of the hypersensitive site revealed a 2- to 4-fold reduction in the steady-state DMAHP transcript levels relative to wildtype controls. Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wildtype allele. Along the same line, Thornton et al. (1997) showed that DMAHP expression in myoblasts, muscle, and myocardium was reduced by the DM mutation in cis, and the magnitude of this effect depended on the extent of the CTG repeat expansion. These observations supported the hypothesis that DMAHP participates in the pathophysiology of DM. </p><p>Since the DM-associated (CTG)n repeat is located in the promoter region of SIX5, immediately downstream of DMPK, Winchester et al. (1999) hypothesized that dysfunction of this gene, which is homologous to the Drosophila eye development gene 'sine oculis,' is primarily responsible for the ophthalmic features of DM. The multicolored iridescent cataract is the most prominent feature of the eye pathology in DM. It is often the first and in some cases the only sign of the disease, occurring at a younger age than is expected for senile cataracts, and occurring in persons who show no muscle symptoms or who carry a premutation (CTG)n repeat allele. In an analysis of the expression of DMPK and SIX5 in normal human fetal and adult eyes, Winchester et al. (1999) found SIX5 transcripts in the adult corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina, and the sclera. SIX5 expression was not detected in fetal eyes. They also reported a restricted but partially overlapping expression pattern for DMPK transcripts and DMPK protein in normal fetal and adult eyes. Winchester et al. (1999) concluded that the expression of SIX5 and not DMPK in the adult lens indicated a role for SIX5 dysfunction in the development of adult-onset cataracts, the most frequently occurring eye phenotype in DM. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Boucher et al. (1995) identified the SIX5 gene in chromosome 19q13.3, centromeric to the DMPK gene (605377). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Branchiootorenal syndrome (BOR2; 610896) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in the EYA1 gene (601653) were identified as a cause of the BOR syndrome. A member of the SIX family of proteins, unc-39 (SIX5), was found to interact directly with eya-1 in Caenorhabditis elegans as identified by high-throughput, yeast 2-hybrid analysis (Li et al., 2004). Hoskins et al. (2007) hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. They therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in 5 individuals with BOR2. Functional analyses of these mutations demonstrated that 2 mutations (600963.0001, 600963.0004) affected EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. </p><p>In 1 of the patients reported by Hoskins et al. (2007) as carrying a mutation in the SIX5 gene (T552M; 600963.0004), Krug et al. (2011) identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused Krug et al. (2011) to reconsider the role of SIX5 in branchiootorenal syndrome etiology. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Klesert et al. (2000) replaced the first exon of Six5 with a beta-galactosidase reporter gene. Histochemical detection of beta-galactosidase activity demonstrated expression as early as 8.5 days postcoitum in the anterior neural folds. Between 10.5 and 15.5 days postcoitum, there was low expression in smooth muscle of stomach, esophagus, and urogenital sinus, and in skeletal muscle of the tongue, as well as scattered expression in the myotome and developing limb muscle. A higher level of expression was seen in the sclerotome, meninges, adrenal gland, and cartilaginous areas of developing bones and trachea. In the eye, expression was evident in the retina, the cornea, the vasculature on the posterior surface of the lens, and faintly in the lens-fiber layer. There was no reliable expression detected in the adult mouse. Disruption of Six5 function did not affect viability or fertility. Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls. Klesert et al. (2000) concluded that Six5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder. </p><p>Sarkar et al. (2000) also studied Six5 expression in mouse. By in situ hybridization, they detected Six5 expression in the adult corneal epithelium and endothelium, inner and outer epithelium of the ciliary body, anterior lens epithelium, ganglion cells, cells of the inner nuclear layer, and photoreceptor cells of the retina. Sarkar et al. (2000) deleted the entire Six5 gene and replaced it with a neo cassette. They found that the rate and severity of cataract formation was inversely related to Six5 dosage and was temporally progressive. Six5 +/- and Six5 -/- mice showed increased steady-state levels of the sodium-potassium-ATPase alpha-1 subunit (182310) and decreased Dm15 mRNA levels. Sarkar et al. (2000) suggested that altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrated that decreased Six5 transcription is important in the etiology of DM. The authors concluded that their data supported the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5. </p><p>Sato et al. (2002) overexpressed a constitutively active form of Six5 in murine P19 embryonal carcinoma cells. Using expression profiling in cDNA arrays, they identified 21 potential target genes whose expression level increased by the treatment. Genes expressed in the somites, skeletal muscles, brain, and meninges comprised the majority, suggesting a role for Six5 in the development and function of mesodermal tissues and brain. One of these genes, Igfbp5 (146734), was also decreased in Six5-deficient mouse fibroblasts, and the response of human IGFBP5 to MyoD (159970)-induced muscle conversion was altered in cells of DM patients. The authors concluded that Six5 is an activator that directs Igfbp5 expression, and hypothesized that reduced SIX5 expression in DM contributes to the DM phenotype. </p><p>The CTG expansion causing DM results in transcriptional silencing of the flanking SIX5 allele. Sarkar et al. (2004) generated Six5 knockout and heterozygous mice by targeted disruption and demonstrated a strict requirement of Six5 for both spermatogenic cell survival and spermiogenesis. Leydig cell hyperproliferation and increased intratesticular testosterone levels were observed in the Six5 -/- mice. Although increased FSH (see 136530) levels were observed in the Six5 +/- and Six5 -/- mice, serum testosterone levels and intratesticular inhibin alpha (INHA; 147380) and inhibin beta-B (INHBB; 147390) levels were not altered in the Six5 mutant animals when compared with controls. Steady-state c-Kit (164920) levels were reduced in the Six5 -/- testis. The authors concluded that decreased c-Kit levels could contribute to the elevated spermatogenic cell apoptosis and Leydig cell hyperproliferation in the Six5 -/- mice. They hypothesized that the reduced SIX5 levels may contribute to the male reproductive defects in DM1. </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>4 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 BRANCHIOOTORENAL SYNDROME 2</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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SIX5, ALA158THR
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<br />
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SNP: rs80356461,
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gnomAD: rs80356461,
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ClinVar: RCV000009129, RCV000782259
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with branchiootorenal syndrome (BOR2; 610896) manifesting bilateral dysplastic kidneys and preauricular tag on the right but no hearing loss, Hoskins et al. (2007) identified a heterozygous 472G-A transition in the SIX5 gene that resulted in an ala158-to-thr (A158T) amino acid substitution. Using yeast 2-hybrid analysis and luciferase assays, Hoskins et al. (2007) showed that this mutation reduced EYA1-SIX5 binding and the ability of the EYA1-SIX5 complex to activate gene transcription. </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 BRANCHIOOTORENAL SYNDROME 2</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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SIX5, ALA296THR
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<br />
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SNP: rs80356462,
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gnomAD: rs80356462,
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ClinVar: RCV000009130, RCV001723554, RCV004752693
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; 610896) who had bilateral dysplastic kidneys and reduced renal function, bilateral hearing loss and cervical fistulae, and right-sided hemifacial microsomia, preauricular sinus, and pinna malformation, Hoskins et al. (2007) identified a heterozygous 886G-A transition in the SIX5 gene that resulted in an ala296-to-thr (A296T) amino acid substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BRANCHIOOTORENAL SYNDROME 2</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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SIX5, GLY365ARG
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<br />
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SNP: rs80356463,
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gnomAD: rs80356463,
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ClinVar: RCV000009131
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with a clinical diagnosis of branchiootorenal syndrome (BOR2; 610896), Hoskins et al. (2007) found a heterozygous 1093G-A transition in the SIX5 gene that resulted in a gly365-to-arg (G365R) amino acid substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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SIX5, THR552MET
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<br />
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SNP: rs80356464,
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gnomAD: rs80356464,
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ClinVar: RCV000009132, RCV001851753
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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>This variant, formerly titled BRANCHIOOTORENAL SYNDROME 2, has been reclassified based on the findings of Krug et al. (2011). </p><p>In 2 unrelated patients with the BOR syndrome (BOR2; 610896), Hoskins et al. (2007) found heterozygosity for the same missense mutation in the SIX5 gene, a 1655C-T transition that resulted in a thr552-to-met (T552M) substitution. One patient had no hearing loss but had bilateral hypoplastic kidneys and cervical fistulae; the second patient had agenesis of the left kidney and hypoplasia of the right kidney, bilateral cervical fistulae, and bilateral hearing loss. Using yeast 2-hybrid analysis and luciferase assays, Hoskins et al. (2007) showed that this mutation reduced EYA1-SIX5 binding and the ability of the EYA1-SIX5 complex to activate gene transcription. </p><p>Krug et al. (2011) demonstrated that one of the patients carrying the T552M mutation had a 3-exon deletion in the EYA1 gene (601653). This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This patient had an affected twin brother and an affected father; both the T552M SIX5 and the 3-exon deletion in EYA1 were found in these family members. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J.
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<strong>A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.</strong>
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Hum. Molec. Genet. 4: 1919-1925, 1995.
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[PubMed: 8595416]
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[Full Text: https://doi.org/10.1093/hmg/4.10.1919]
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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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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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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Heath, S. K., Carne, S., Hoyle, C., Johnson, K. J., Wells, D. J.
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<strong>Characterisation of expression of mDMAHP, a homeodomain-encoding gene at the murine DM locus.</strong>
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Hum. Molec. Genet. 6: 651-657, 1997.
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[PubMed: 9158137]
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[Full Text: https://doi.org/10.1093/hmg/6.5.651]
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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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Hoskins, B. E., Cramer, C. H., II, Silvius, D., Zou, D., Raymond, R. M., Jr., Orten, D. J., Kimberling, W. J., Smith, R. J. H., Weil, D., Petit, C., Otto, E. A., Xu, P.-X., Hildebrandt, F.
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<strong>Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome.</strong>
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Am. J. Hum. Genet. 80: 800-804, 2007.
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[PubMed: 17357085]
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[Full Text: https://doi.org/10.1086/513322]
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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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Klesert, T. R., Cho, D. H., Clark, J. I., Maylie, J., Adelman, J., Snider, L., Yuen, E. C., Soriano, P., Tapscott, S. J.
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<strong>Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.</strong>
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Ada Hamosh - updated : 12/5/2014<br>Victor A. McKusick - updated : 3/27/2007<br>George E. Tiller - updated : 9/21/2006<br>George E. Tiller - updated : 12/13/2002<br>Ada Hamosh - updated : 4/27/2000<br>Victor A. McKusick - updated : 3/19/1999<br>Victor A. McKusick - updated : 8/1/1997<br>Victor A. McKusick - updated : 6/23/1997
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