3506 lines
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- *612659 - REGULATORY FACTOR X, 6; RFX6
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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">*612659</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/612659">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000185002;t=ENST00000332958" 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=222546" 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=612659" 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=ENSG00000185002;t=ENST00000332958" 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_173560,XM_011535589,XM_017010477" 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_173560" 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=612659" 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=11490&isoform_id=11490_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/RFX6" 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/24660190,119568597,119568598,166225159,258547126,767942256,1034649096,2462606840,2462606842" 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/Q8HWS3" 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=222546" 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=ENSG00000185002;t=ENST00000332958" 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=RFX6" 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=RFX6" 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+222546" 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/RFX6" 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:222546" 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/222546" 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=chr6&hgg_gene=ENST00000332958.3&hgg_start=116877242&hgg_end=116932161&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:21478" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:21478" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=612659[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=612659[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/RFX6/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/ENSG00000185002" 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=RFX6" 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=RFX6" 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=RFX6" 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=RFX6&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/PA162401254" 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:21478" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2445208" 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/RFX6#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:2445208" 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/222546/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=222546" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041014-299" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:222546" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=RFX6&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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612659
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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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REGULATORY FACTOR X, 6; RFX6
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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RFXDC1
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RFX6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RFX6</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/6/807?start=-3&limit=10&highlight=807">6q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:116877242-116932161&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'})">6:116,877,242-116,932,161</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">
|
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<a href="/geneMap/6/807?start=-3&limit=10&highlight=807">
|
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6q22.1
|
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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">
|
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Mitchell-Riley syndrome
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/615710"> 615710 </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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</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>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/612659" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/612659" 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>RFX6 is a member of the regulatory factor X (RFX) family of transcription factors (see RFX1, <a href="/entry/600006">600006</a>) (<a href="#1" class="mim-tip-reference" title="Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N. <strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong> BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18673564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18673564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18673564[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/10.1186/1471-2148-8-226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18673564">Aftab et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18673564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By database analysis to search for sequences containing the RFX DNA-binding domain (DBD), <a href="#1" class="mim-tip-reference" title="Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N. <strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong> BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18673564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18673564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18673564[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/10.1186/1471-2148-8-226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18673564">Aftab et al. (2008)</a> identified RFX6 and 5 corresponding mammalian orthologs. The deduced 928-amino acid protein is a member of the winged helix family of DNA-binding proteins with high similarity over the DBDs and highest overall similarity to RFX4 (<a href="/entry/603958">603958</a>). RFX6 contains a winged helix region, predicted to interact with the major groove of DNA, and a conserved helix H3 predicted to interact with the minor groove. EST database analysis showed expression of RFX6 primarily in pancreas with lower expression in liver, which was confirmed by analysis of mouse SAGE libraries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18673564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N. <strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong> BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18673564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18673564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18673564[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/10.1186/1471-2148-8-226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18673564">Aftab et al. (2008)</a> determined that the RFX6 gene contains 19 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18673564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By database analysis, <a href="#1" class="mim-tip-reference" title="Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N. <strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong> BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18673564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18673564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18673564[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/10.1186/1471-2148-8-226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18673564">Aftab et al. (2008)</a> mapped the RFX6 gene to chromosome 6q22.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18673564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By large-scale yeast 2-hybrid proteome analysis of protein interactions, <a href="#1" class="mim-tip-reference" title="Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N. <strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong> BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18673564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18673564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18673564[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/10.1186/1471-2148-8-226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18673564">Aftab et al. (2008)</a> determined that RFX6 interacted with RFX family members RFX2 (<a href="/entry/142765">142765</a>) and RFX3 (<a href="/entry/601337">601337</a>), in addition to interactions with DTX1 (<a href="/entry/602582">602582</a>), DTX2 (<a href="/entry/613141">613141</a>), FHL3 (<a href="/entry/602790">602790</a>), CCNK (<a href="/entry/603544">603544</a>), and SS18L1 (<a href="/entry/606472">606472</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18673564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> demonstrated that the transcription factor Rfx6 in mice directs islet cell differentiation downstream of Neurog3 (<a href="/entry/604882">604882</a>). Mice lacking Rfx6 failed to generate any of the normal islet cell types, except for pancreatic polypeptide-producing cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Vaisanen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., and 10 others. <strong>A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.</strong> Nature Genet. 46: 126-135, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24390282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24390282</a>] [<a href="https://doi.org/10.1038/ng.2862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24390282">Huang et al. (2014)</a> found that an evolutionarily conserved region in intron 4 of the RFX6 gene functions as a transcriptional enhancer with allele-specific activity. The T allele of a single-nucleotide polymorphism (SNP) in the region, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs339331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs339331</a>, enhances HOXB13 (<a href="/entry/604607">604607</a>) chromatin binding and drives allele-specific upregulation of RFX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24390282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify early disease-driving events in type 2 diabetes (T2D; see <a href="/entry/125853">125853</a>), <a href="#9" class="mim-tip-reference" title="Walker, J. T., Saunders, D. C., Rai, V., Chen, H.-H., Orchard, P., Dai, C., Pettway, Y. D., Hopkirk, A. L., Reihsmann, C. V., Tao, Y., Fan, S., Shrestha, S., and 21 others. <strong>Genetic risk converges on regulatory networks mediating early type 2 diabetes.</strong> Nature 624: 621-629, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38049589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38049589</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38049589[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-023-06693-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38049589">Walker et al. (2023)</a> performed traditional and multiplexed pancreatic tissue imaging, sorted islet cell transcriptomics, and islet cell functional analysis of early-stage T2D and control donors. By integrating diverse modalities, <a href="#9" class="mim-tip-reference" title="Walker, J. T., Saunders, D. C., Rai, V., Chen, H.-H., Orchard, P., Dai, C., Pettway, Y. D., Hopkirk, A. L., Reihsmann, C. V., Tao, Y., Fan, S., Shrestha, S., and 21 others. <strong>Genetic risk converges on regulatory networks mediating early type 2 diabetes.</strong> Nature 624: 621-629, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38049589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38049589</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38049589[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-023-06693-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38049589">Walker et al. (2023)</a> showed that early-stage T2D is characterized by beta cell-intrinsic defects that could be divided into different gene regulatory modules. They identified RFX6 as a beta-cell hub gene and showed multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by beta cells. RFX6 expression is reduced in T2D. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38049589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> analyzed the candidate gene RFX6 in 6 patients with neonatal diabetes, hypoplastic or annular pancreas, intestinal atresia and/or malrotation, and gallbladder hypoplasia or agenesis (Mitchell-Riley syndrome; MTCHRS; <a href="/entry/615710">615710</a>), and identified homozygosity or compound heterozygosity for RFX6 mutations in 5 of the 6 probands (<a href="#0001">612659.0001</a>-<a href="#0006">612659.0006</a>). The authors noted that the 3 patients with mutations resulting in complete loss of function died within the first few months of life, whereas the 2 patients with mutations associated with residual function were still alive at 4.5 and 9 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In two 9-year-old Turkish double first cousins with Mitchell-Riley syndrome, <a href="#7" class="mim-tip-reference" title="Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J. <strong>Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.</strong> Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26264437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26264437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26264437[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2015.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26264437">Sansbury et al. (2015)</a> identified compound heterozygosity for 2 nonsense mutations in the RFX6 gene (R726X, <a href="#0007">612659.0007</a>; R866X, <a href="#0008">612659.0008</a>). Noting that the 2 affected cousins exhibited a relatively milder phenotype than previously reported patients, the authors suggested that their mutations might result in incomplete inactivation of RFX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26264437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prostate Cancer Susceptibility</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Vaisanen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., and 10 others. <strong>A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.</strong> Nature Genet. 46: 126-135, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24390282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24390282</a>] [<a href="https://doi.org/10.1038/ng.2862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24390282">Huang et al. (2014)</a> found that a prostate cancer (<a href="/entry/176807">176807</a>) risk-associated SNP on chromosome 6q22, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs339331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs339331</a>, lies within an evolutionarily conserved region in intron 4 of the transcription factor RFX6 gene that functions as a HOXB13-binding site. The risk-associated T allele at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs339331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs339331</a> increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration, and invasion. Clinical data indicated that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis, and risk of biochemical relapse. <a href="#3" class="mim-tip-reference" title="Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Vaisanen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., and 10 others. <strong>A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.</strong> Nature Genet. 46: 126-135, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24390282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24390282</a>] [<a href="https://doi.org/10.1038/ng.2862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24390282">Huang et al. (2014)</a> observed a significant association between the risk-associated T allele at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs339331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs339331</a> and increased RFX6 mRNA levels in human prostate tumors. The authors concluded that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs339331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs339331</a> affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24390282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Patel, K. A., Kettunen, J., Laakso, M., Stancakova, A., Laver, T. W., Colclough, K., Johnson, M. B., Abramowicz, M., Groop, L., Miettinen, P. J., Shepherd, M. H., Flanagan, S. E., Ellard, S., Inagaki, N., Hattersley, A. T., Tuomi, T., Cnop, M., Weedon, M. N. <strong>Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.</strong> Nature Commun. 8: 888, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29026101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29026101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29026101[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-00895-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29026101">Patel et al. (2017)</a> sequenced a cohort of European patients with maturity-onset diabetes of the young (MODY; see <a href="/entry/606391">606391</a>) and compared them with population controls. In the discovery cohort of 36 patients, 2 unrelated probands were identified with heterozygous nonsense variants in RFX6. <a href="#6" class="mim-tip-reference" title="Patel, K. A., Kettunen, J., Laakso, M., Stancakova, A., Laver, T. W., Colclough, K., Johnson, M. B., Abramowicz, M., Groop, L., Miettinen, P. J., Shepherd, M. H., Flanagan, S. E., Ellard, S., Inagaki, N., Hattersley, A. T., Tuomi, T., Cnop, M., Weedon, M. N. <strong>Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.</strong> Nature Commun. 8: 888, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29026101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29026101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29026101[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-017-00895-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29026101">Patel et al. (2017)</a> found that RFX6 protein truncating variants were enriched in the MODY discovery and replication cohorts compared to the European control population within ExAC (odds ratio (OR) = 131, p = 1 x 10(-4)) and found similar results in replication cohorts of 348 non-Finnish European individuals (OR = 43, p = 5 x 10(-5)) and 80 Finnish individuals (OR = 22, p = 1 x 10(-6)). MODY segregated with variants reported in the 2 families, but with later age at onset (32, range 24 to 46) and incomplete penetrance compared with other causes of MODY. The hyperglycemia was associated with beta-cell dysfunction and was associated with lower levels of gastric inhibitory polypeptide (GIP; <a href="/entry/137240">137240</a>) in the fasted and stimulated state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29026101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> generated Rfx6-null mice. They also generated mice in which the Rfx6 locus is marked by beta-galactosidase expression, and these studies showed that Rfx6 is initially expressed broadly in the definitive endoderm after gastrulation and becomes restricted to the gut and pancreatic bud at midgestation. Furthermore, Rfx6 is reactivated by Neurog3 in islet progenitor cells and is also restricted to pancreatic islets in the mature pancreas. Rfx6-null mice were born at the expected mendelian ratio, but failed to feed normally, exhibited gross bowel distention to small bowel obstruction, and died within 2 days postpartum. Some of the Rfx6-null mice also had reduced pancreas size. To test for effects on gene expression before birth, <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> collected RNA from embryonic day 17.5 pancreata, and showed that the null mice had almost no expression of islet hormone genes, except for pancreatic polypeptide (Ppy). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776514;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776514" 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=rs587776514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a female infant, born of consanguineous Pakistani parents, with neonatal diabetes, duodenal and jejunal atresia, annular pancreas, and gallbladder agenesis (MTCHRS; <a href="/entry/615710">615710</a>), originally reported by <a href="#5" class="mim-tip-reference" title="Mitchell, J., Punthakee, Z., Lo, B., Bernard, C., Chong, K., Newman, C., Cartier, L., Desilets, V., Cutz, E., Hansen, I. L., Riley, P., Polychronakos, C. <strong>Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.</strong> Diabetologia 47: 2160-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15592663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15592663</a>] [<a href="https://doi.org/10.1007/s00125-004-1576-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15592663">Mitchell et al. (2004)</a> as 'family 1,' <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> identified homozygosity for a +2T-C transition at the donor splice site in intron 2 of the RFX6 gene. The unaffected parents were heterozygous for the mutation. Amplification of RFX6 mRNA from autopsy pancreas from the patient, who died of multiorgan failure at 6.5 months of life, demonstrated that there was no normally spliced transcript, and no RNA was detected from exons 1 and 2, upstream of the splicing mutation, consistent with nonsense-mediated decay. The patient's similarly affected deceased older brother, who had neonatal diabetes, patent foramen ovale, duodenal and jejeunal atresia, and hypoplastic pancreas and gallbladder, died at 5 months of age with multiorgan failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20148032+15592663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587776515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776515;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/rs587776515?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=rs587776515" 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=rs587776515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a female infant who was conceived by in vitro fertilization with a donated egg and had neonatal hyperglycemia, duodenal web with malrotation, and hypoplastic pancreas and gallbladder (MTCHRS; <a href="/entry/615710">615710</a>), originally reported by <a href="#5" class="mim-tip-reference" title="Mitchell, J., Punthakee, Z., Lo, B., Bernard, C., Chong, K., Newman, C., Cartier, L., Desilets, V., Cutz, E., Hansen, I. L., Riley, P., Polychronakos, C. <strong>Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.</strong> Diabetologia 47: 2160-2167, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15592663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15592663</a>] [<a href="https://doi.org/10.1007/s00125-004-1576-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15592663">Mitchell et al. (2004)</a>, <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> identified compound heterozygosity for splice site mutations in the RFX6 gene: a -12A-G transition at the acceptor site in intron 1 and a +2T-G transversion at the donor site in intron 6 (<a href="#0003">612659.0003</a>). The patient was alive at 9 years of age and intermittently off insulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20148032+15592663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MITCHELL-RILEY SYNDROME</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">rs587776516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776516;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776516" 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=rs587776516" 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=RCV000000527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000527</a>
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<p>For discussion of the +2T-G transversion at the donor site in intron 6 of the RFX6 gene that was found in a patient with Mitchell-Riley syndrome (MTCHRS; <a href="/entry/615710">615710</a>) by <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a>, see <a href="#0002">612659.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 MITCHELL-RILEY SYNDROME</strong>
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RFX6, SER217PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607012;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607012" 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=rs267607012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000528" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000528" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000528</a>
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<p>In a Pakistani girl, born to first-cousin parents, who had neonatal diabetes, duodenal atresia, gallbladder agenesis, and an anteriorly placed anus (MTCHRS; <a href="/entry/615710">615710</a>), previously reported by <a href="#2" class="mim-tip-reference" title="Chappell, L., Gorman, S., Campbell, F., Ellard, S., Rice, G., Dobbie, A., Crow, Y. <strong>A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis.</strong> Am. J. Med. Genet. 146A: 1713-1717, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18512226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18512226</a>] [<a href="https://doi.org/10.1002/ajmg.a.32304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18512226">Chappell et al. (2008)</a>, <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> identified homozygosity for a ser217-to-pro (S217P) substitution in exon 5 of the RFX6 gene, at a highly conserved residue between the DNA-binding and dimerization domains. Functional analysis showed that S217P only modestly reduced DNA binding and did not affect dimer formation. The patient, who had no pancreatic abnormality by ultrasound, was alive at 4.5 years and insulin dependent. The unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20148032+18512226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 MITCHELL-RILEY SYNDROME</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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RFX6, ARG181GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607013 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607013;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607013" 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=rs267607013" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000529 OR RCV003415604" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000529, RCV003415604" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000529...</a>
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<p>In a male infant, born to consanguineous parents of Moroccan descent, who had congenital hemochromatosis, neonatal diabetes, duodenal and jejunal atresia, intestinal malrotation, hypoplastic pancreas, and gallbladder agenesis (MTCHRS; <a href="/entry/615710">615710</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Martinovici, D., Ransy, V., Eijnden, S. V., Ridremont, C., Pardou, A., Cassart, M., Avni, F., Donner, C., Lingier, P., Mathieu, A., Gulbis, B., De Brouckere, V., Cnop, M., Abramowicz, M., Desir, J. <strong>Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn.</strong> Europ. J. Med. Genet. 53: 25-28, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19887127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19887127</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.10.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19887127">Martinovici et al. (2010)</a>, <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> identified homozygosity for an arg181-to-gln (R181Q) substitution in exon 4 of the RFX6 gene. Functional analysis demonstrated that the R181Q mutation, which alters a highly conserved amino acid in the DNA-binding domain, completely abrogates DNA binding. The patient died in the third month of life. Both the mother, who had insulin-dependent diabetes, and the father, who had impaired fasting glucose, were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19887127+20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 MITCHELL-RILEY SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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RFX6, 13-BP DEL, EXON/INTRON 7
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776517 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776517;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776517" 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=rs587776517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000000530" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000000530" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000000530</a>
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<span class="mim-text-font">
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<p>In a male infant, born to nonconsanguineous parents, who had intrauterine growth retardation and duodenal atresia and was diagnosed with neonatal diabetes on day 2 of life (MTCHRS; <a href="/entry/615710">615710</a>), <a href="#8" class="mim-tip-reference" title="Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others. <strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong> Nature 463: 775-780, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20148032">Smith et al. (2010)</a> identified homozygosity for an out-of-frame 13-bp deletion encompassing the last 5 nucleotides of exon 7 and the first 8 nucleotides of intron 7 of the RFX6 gene. The patient had a complicated course and died of gastrointestinal hemorrhage at 2.5 months of age. Both the mother, who had gestational diabetes during the pregnancy, and the father, who had been diagnosed with type 1 diabetes, were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20148032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 MITCHELL-RILEY SYNDROME</strong>
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RFX6, ARG726TER
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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> rs144648002 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144648002;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/rs144648002?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=rs144648002" 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=rs144648002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000208877 OR RCV002517416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208877, RCV002517416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208877...</a>
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<span class="mim-text-font">
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<p>In two 9-year-old Turkish double first cousins with Mitchell-Riley syndrome (MTCHRS; <a href="/entry/615710">615710</a>), <a href="#7" class="mim-tip-reference" title="Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J. <strong>Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.</strong> Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26264437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26264437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26264437[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2015.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26264437">Sansbury et al. (2015)</a> identified compound heterozygosity for 2 mutations in the RFX6 gene: a c.2176C-T transition in exon 17, resulting in an arg726-to-ter (R726X) substitution, and a c.2596C-T transition in exon 18, resulting in an arg866-to-ter (R866X; <a href="#0008">612659.0008</a>) substitution. The 4 parents were each heterozygous for 1 of the mutations. Noting that the 2 affected cousins exhibited a relatively milder phenotype than previously reported patients, including later onset of diabetes, no liver pathology apart from absent gallbladder in 1 patient, and a greater age of survival, the authors suggested that their mutations might result in incomplete inactivation of RFX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26264437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 MITCHELL-RILEY SYNDROME</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> rs749827445 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749827445;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/rs749827445?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=rs749827445" 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=rs749827445" 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=RCV000208878 OR RCV002272175" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208878, RCV002272175" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208878...</a>
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<p>For discussion of the c.2596C-T transition in exon 18 of the RFX6 gene, resulting in an arg866-to-ter (R866X) substitution, that was found in compound heterozygous state in 2 Turkish cousins with Mitchell-Reilly syndrome (MTCHRS; <a href="/entry/615710">615710</a>) by <a href="#7" class="mim-tip-reference" title="Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J. <strong>Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.</strong> Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26264437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26264437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26264437[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2015.161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26264437">Sansbury et al. (2015)</a>, see <a href="#0007">612659.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26264437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N.
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<strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong>
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[<a href="https://doi.org/10.1186/1471-2148-8-226" target="_blank">Full Text</a>]
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Chappell, L., Gorman, S., Campbell, F., Ellard, S., Rice, G., Dobbie, A., Crow, Y.
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<strong>A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis.</strong>
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Am. J. Med. Genet. 146A: 1713-1717, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18512226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18512226</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18512226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32304" target="_blank">Full Text</a>]
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Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Vaisanen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., and 10 others.
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<strong>A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.</strong>
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Nature Genet. 46: 126-135, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24390282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24390282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24390282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2862" target="_blank">Full Text</a>]
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Martinovici, D., Ransy, V., Eijnden, S. V., Ridremont, C., Pardou, A., Cassart, M., Avni, F., Donner, C., Lingier, P., Mathieu, A., Gulbis, B., De Brouckere, V., Cnop, M., Abramowicz, M., Desir, J.
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<strong>Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn.</strong>
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Europ. J. Med. Genet. 53: 25-28, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19887127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19887127</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19887127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2009.10.004" target="_blank">Full Text</a>]
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Mitchell, J., Punthakee, Z., Lo, B., Bernard, C., Chong, K., Newman, C., Cartier, L., Desilets, V., Cutz, E., Hansen, I. L., Riley, P., Polychronakos, C.
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<strong>Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.</strong>
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Diabetologia 47: 2160-2167, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15592663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15592663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15592663" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Patel, K. A., Kettunen, J., Laakso, M., Stancakova, A., Laver, T. W., Colclough, K., Johnson, M. B., Abramowicz, M., Groop, L., Miettinen, P. J., Shepherd, M. H., Flanagan, S. E., Ellard, S., Inagaki, N., Hattersley, A. T., Tuomi, T., Cnop, M., Weedon, M. N.
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<strong>Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.</strong>
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Nature Commun. 8: 888, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29026101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29026101</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29026101[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=29026101" 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/s41467-017-00895-9" target="_blank">Full Text</a>]
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Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J.
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<strong>Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.</strong>
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Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26264437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26264437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26264437[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=26264437" 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/ejhg.2015.161" target="_blank">Full Text</a>]
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Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others.
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<strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong>
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Nature 463: 775-780, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20148032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20148032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20148032[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=20148032" 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/nature08748" target="_blank">Full Text</a>]
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Walker, J. T., Saunders, D. C., Rai, V., Chen, H.-H., Orchard, P., Dai, C., Pettway, Y. D., Hopkirk, A. L., Reihsmann, C. V., Tao, Y., Fan, S., Shrestha, S., and 21 others.
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<strong>Genetic risk converges on regulatory networks mediating early type 2 diabetes.</strong>
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Nature 624: 621-629, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38049589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38049589</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38049589[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=38049589" 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/s41586-023-06693-2" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 03/20/2024
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 01/24/2023<br>Marla J. F. O'Neill - updated : 03/07/2016<br>Ada Hamosh - updated : 11/18/2014<br>Marla J. F. O'Neill - updated : 4/9/2014<br>Marla J. F. O'Neill - updated : 3/4/2010<br>Ada Hamosh - updated : 3/2/2010
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</span>
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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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Dorothy S. Reilly : 3/12/2009
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<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 : 11/22/2024
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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 : 03/20/2024<br>carol : 01/26/2023<br>alopez : 01/24/2023<br>carol : 03/07/2016<br>mcolton : 5/18/2015<br>alopez : 11/18/2014<br>carol : 4/10/2014<br>carol : 4/9/2014<br>carol : 4/9/2014<br>carol : 3/4/2010<br>terry : 3/2/2010<br>mgross : 11/23/2009<br>wwang : 3/12/2009
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 612659
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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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REGULATORY FACTOR X, 6; RFX6
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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RFXDC1
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</span>
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</h4>
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</div>
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<div>
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<br />
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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: RFX6</em></strong>
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</span>
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</p>
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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: 6q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:116,877,242-116,932,161 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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6q22.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Mitchell-Riley syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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615710
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>RFX6 is a member of the regulatory factor X (RFX) family of transcription factors (see RFX1, 600006) (Aftab et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By database analysis to search for sequences containing the RFX DNA-binding domain (DBD), Aftab et al. (2008) identified RFX6 and 5 corresponding mammalian orthologs. The deduced 928-amino acid protein is a member of the winged helix family of DNA-binding proteins with high similarity over the DBDs and highest overall similarity to RFX4 (603958). RFX6 contains a winged helix region, predicted to interact with the major groove of DNA, and a conserved helix H3 predicted to interact with the minor groove. EST database analysis showed expression of RFX6 primarily in pancreas with lower expression in liver, which was confirmed by analysis of mouse SAGE libraries. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Aftab et al. (2008) determined that the RFX6 gene contains 19 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By database analysis, Aftab et al. (2008) mapped the RFX6 gene to chromosome 6q22.2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By large-scale yeast 2-hybrid proteome analysis of protein interactions, Aftab et al. (2008) determined that RFX6 interacted with RFX family members RFX2 (142765) and RFX3 (601337), in addition to interactions with DTX1 (602582), DTX2 (613141), FHL3 (602790), CCNK (603544), and SS18L1 (606472). </p><p>Smith et al. (2010) demonstrated that the transcription factor Rfx6 in mice directs islet cell differentiation downstream of Neurog3 (604882). Mice lacking Rfx6 failed to generate any of the normal islet cell types, except for pancreatic polypeptide-producing cells. </p><p>Huang et al. (2014) found that an evolutionarily conserved region in intron 4 of the RFX6 gene functions as a transcriptional enhancer with allele-specific activity. The T allele of a single-nucleotide polymorphism (SNP) in the region, rs339331, enhances HOXB13 (604607) chromatin binding and drives allele-specific upregulation of RFX6. </p><p>To identify early disease-driving events in type 2 diabetes (T2D; see 125853), Walker et al. (2023) performed traditional and multiplexed pancreatic tissue imaging, sorted islet cell transcriptomics, and islet cell functional analysis of early-stage T2D and control donors. By integrating diverse modalities, Walker et al. (2023) showed that early-stage T2D is characterized by beta cell-intrinsic defects that could be divided into different gene regulatory modules. They identified RFX6 as a beta-cell hub gene and showed multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by beta cells. RFX6 expression is reduced in T2D. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Mitchell-Riley Syndrome</em></strong></p><p>
|
|
Smith et al. (2010) analyzed the candidate gene RFX6 in 6 patients with neonatal diabetes, hypoplastic or annular pancreas, intestinal atresia and/or malrotation, and gallbladder hypoplasia or agenesis (Mitchell-Riley syndrome; MTCHRS; 615710), and identified homozygosity or compound heterozygosity for RFX6 mutations in 5 of the 6 probands (612659.0001-612659.0006). The authors noted that the 3 patients with mutations resulting in complete loss of function died within the first few months of life, whereas the 2 patients with mutations associated with residual function were still alive at 4.5 and 9 years, respectively. </p><p>In two 9-year-old Turkish double first cousins with Mitchell-Riley syndrome, Sansbury et al. (2015) identified compound heterozygosity for 2 nonsense mutations in the RFX6 gene (R726X, 612659.0007; R866X, 612659.0008). Noting that the 2 affected cousins exhibited a relatively milder phenotype than previously reported patients, the authors suggested that their mutations might result in incomplete inactivation of RFX6. </p><p><strong><em>Prostate Cancer Susceptibility</em></strong></p><p>
|
|
Huang et al. (2014) found that a prostate cancer (176807) risk-associated SNP on chromosome 6q22, rs339331, lies within an evolutionarily conserved region in intron 4 of the transcription factor RFX6 gene that functions as a HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration, and invasion. Clinical data indicated that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis, and risk of biochemical relapse. Huang et al. (2014) observed a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. The authors concluded that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Patel et al. (2017) sequenced a cohort of European patients with maturity-onset diabetes of the young (MODY; see 606391) and compared them with population controls. In the discovery cohort of 36 patients, 2 unrelated probands were identified with heterozygous nonsense variants in RFX6. Patel et al. (2017) found that RFX6 protein truncating variants were enriched in the MODY discovery and replication cohorts compared to the European control population within ExAC (odds ratio (OR) = 131, p = 1 x 10(-4)) and found similar results in replication cohorts of 348 non-Finnish European individuals (OR = 43, p = 5 x 10(-5)) and 80 Finnish individuals (OR = 22, p = 1 x 10(-6)). MODY segregated with variants reported in the 2 families, but with later age at onset (32, range 24 to 46) and incomplete penetrance compared with other causes of MODY. The hyperglycemia was associated with beta-cell dysfunction and was associated with lower levels of gastric inhibitory polypeptide (GIP; 137240) in the fasted and stimulated state. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>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">
|
|
<p>Smith et al. (2010) generated Rfx6-null mice. They also generated mice in which the Rfx6 locus is marked by beta-galactosidase expression, and these studies showed that Rfx6 is initially expressed broadly in the definitive endoderm after gastrulation and becomes restricted to the gut and pancreatic bud at midgestation. Furthermore, Rfx6 is reactivated by Neurog3 in islet progenitor cells and is also restricted to pancreatic islets in the mature pancreas. Rfx6-null mice were born at the expected mendelian ratio, but failed to feed normally, exhibited gross bowel distention to small bowel obstruction, and died within 2 days postpartum. Some of the Rfx6-null mice also had reduced pancreas size. To test for effects on gene expression before birth, Smith et al. (2010) collected RNA from embryonic day 17.5 pancreata, and showed that the null mice had almost no expression of islet hormone genes, except for pancreatic polypeptide (Ppy). </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">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>8 Selected Examples):</strong>
|
|
</span>
|
|
</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">
|
|
<strong>.0001 MITCHELL-RILEY SYNDROME</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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RFX6, IVS2, T-C, +2
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<br />
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SNP: rs587776514,
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ClinVar: RCV000000525
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a female infant, born of consanguineous Pakistani parents, with neonatal diabetes, duodenal and jejunal atresia, annular pancreas, and gallbladder agenesis (MTCHRS; 615710), originally reported by Mitchell et al. (2004) as 'family 1,' Smith et al. (2010) identified homozygosity for a +2T-C transition at the donor splice site in intron 2 of the RFX6 gene. The unaffected parents were heterozygous for the mutation. Amplification of RFX6 mRNA from autopsy pancreas from the patient, who died of multiorgan failure at 6.5 months of life, demonstrated that there was no normally spliced transcript, and no RNA was detected from exons 1 and 2, upstream of the splicing mutation, consistent with nonsense-mediated decay. The patient's similarly affected deceased older brother, who had neonatal diabetes, patent foramen ovale, duodenal and jejeunal atresia, and hypoplastic pancreas and gallbladder, died at 5 months of age with multiorgan failure. </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 MITCHELL-RILEY SYNDROME</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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RFX6, IVS1AS, A-G, -12
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<br />
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SNP: rs587776515,
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gnomAD: rs587776515,
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ClinVar: RCV000000526, RCV001225303
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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 female infant who was conceived by in vitro fertilization with a donated egg and had neonatal hyperglycemia, duodenal web with malrotation, and hypoplastic pancreas and gallbladder (MTCHRS; 615710), originally reported by Mitchell et al. (2004), Smith et al. (2010) identified compound heterozygosity for splice site mutations in the RFX6 gene: a -12A-G transition at the acceptor site in intron 1 and a +2T-G transversion at the donor site in intron 6 (612659.0003). The patient was alive at 9 years of age and intermittently off insulin. </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 MITCHELL-RILEY SYNDROME</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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RFX6, IVS6, T-G, +2
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<br />
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SNP: rs587776516,
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ClinVar: RCV000000527
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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>For discussion of the +2T-G transversion at the donor site in intron 6 of the RFX6 gene that was found in a patient with Mitchell-Riley syndrome (MTCHRS; 615710) by Smith et al. (2010), see 612659.0002. </p>
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</span>
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</div>
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<span class="mim-font">
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<strong>.0004 MITCHELL-RILEY SYNDROME</strong>
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</h4>
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<span class="mim-text-font">
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RFX6, SER217PRO
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<br />
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SNP: rs267607012,
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ClinVar: RCV000000528
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<p>In a Pakistani girl, born to first-cousin parents, who had neonatal diabetes, duodenal atresia, gallbladder agenesis, and an anteriorly placed anus (MTCHRS; 615710), previously reported by Chappell et al. (2008), Smith et al. (2010) identified homozygosity for a ser217-to-pro (S217P) substitution in exon 5 of the RFX6 gene, at a highly conserved residue between the DNA-binding and dimerization domains. Functional analysis showed that S217P only modestly reduced DNA binding and did not affect dimer formation. The patient, who had no pancreatic abnormality by ultrasound, was alive at 4.5 years and insulin dependent. The unaffected parents were heterozygous for the mutation. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 MITCHELL-RILEY SYNDROME</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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RFX6, ARG181GLN
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<br />
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SNP: rs267607013,
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ClinVar: RCV000000529, RCV003415604
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<p>In a male infant, born to consanguineous parents of Moroccan descent, who had congenital hemochromatosis, neonatal diabetes, duodenal and jejunal atresia, intestinal malrotation, hypoplastic pancreas, and gallbladder agenesis (MTCHRS; 615710), originally reported by Martinovici et al. (2010), Smith et al. (2010) identified homozygosity for an arg181-to-gln (R181Q) substitution in exon 4 of the RFX6 gene. Functional analysis demonstrated that the R181Q mutation, which alters a highly conserved amino acid in the DNA-binding domain, completely abrogates DNA binding. The patient died in the third month of life. Both the mother, who had insulin-dependent diabetes, and the father, who had impaired fasting glucose, were heterozygous for the mutation. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0006 MITCHELL-RILEY SYNDROME</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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RFX6, 13-BP DEL, EXON/INTRON 7
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<br />
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SNP: rs587776517,
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ClinVar: RCV000000530
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a male infant, born to nonconsanguineous parents, who had intrauterine growth retardation and duodenal atresia and was diagnosed with neonatal diabetes on day 2 of life (MTCHRS; 615710), Smith et al. (2010) identified homozygosity for an out-of-frame 13-bp deletion encompassing the last 5 nucleotides of exon 7 and the first 8 nucleotides of intron 7 of the RFX6 gene. The patient had a complicated course and died of gastrointestinal hemorrhage at 2.5 months of age. Both the mother, who had gestational diabetes during the pregnancy, and the father, who had been diagnosed with type 1 diabetes, were heterozygous for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 MITCHELL-RILEY SYNDROME</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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RFX6, ARG726TER
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<br />
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SNP: rs144648002,
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gnomAD: rs144648002,
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ClinVar: RCV000208877, RCV002517416
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In two 9-year-old Turkish double first cousins with Mitchell-Riley syndrome (MTCHRS; 615710), Sansbury et al. (2015) identified compound heterozygosity for 2 mutations in the RFX6 gene: a c.2176C-T transition in exon 17, resulting in an arg726-to-ter (R726X) substitution, and a c.2596C-T transition in exon 18, resulting in an arg866-to-ter (R866X; 612659.0008) substitution. The 4 parents were each heterozygous for 1 of the mutations. Noting that the 2 affected cousins exhibited a relatively milder phenotype than previously reported patients, including later onset of diabetes, no liver pathology apart from absent gallbladder in 1 patient, and a greater age of survival, the authors suggested that their mutations might result in incomplete inactivation of RFX6. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 MITCHELL-RILEY SYNDROME</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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RFX6, ARG866TER
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<br />
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SNP: rs749827445,
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gnomAD: rs749827445,
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ClinVar: RCV000208878, RCV002272175
|
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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>For discussion of the c.2596C-T transition in exon 18 of the RFX6 gene, resulting in an arg866-to-ter (R866X) substitution, that was found in compound heterozygous state in 2 Turkish cousins with Mitchell-Reilly syndrome (MTCHRS; 615710) by Sansbury et al. (2015), see 612659.0007. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</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">
|
|
Aftab, S., Semenec, L., Chu, J. S.-C., Chen, N.
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|
<strong>Identification and characterization of novel human tissue-specific RFX transcription factors.</strong>
|
|
BMC Evol. Biol. 8: 226, 2008. Note: Electronic Article.
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[PubMed: 18673564]
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[Full Text: https://doi.org/10.1186/1471-2148-8-226]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Chappell, L., Gorman, S., Campbell, F., Ellard, S., Rice, G., Dobbie, A., Crow, Y.
|
|
<strong>A further example of a distinctive autosomal recessive syndrome comprising neonatal diabetes mellitus, intestinal atresias and gall bladder agenesis.</strong>
|
|
Am. J. Med. Genet. 146A: 1713-1717, 2008.
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[PubMed: 18512226]
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[Full Text: https://doi.org/10.1002/ajmg.a.32304]
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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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Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Vaisanen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., and 10 others.
|
|
<strong>A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding.</strong>
|
|
Nature Genet. 46: 126-135, 2014.
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[PubMed: 24390282]
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[Full Text: https://doi.org/10.1038/ng.2862]
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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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Martinovici, D., Ransy, V., Eijnden, S. V., Ridremont, C., Pardou, A., Cassart, M., Avni, F., Donner, C., Lingier, P., Mathieu, A., Gulbis, B., De Brouckere, V., Cnop, M., Abramowicz, M., Desir, J.
|
|
<strong>Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn.</strong>
|
|
Europ. J. Med. Genet. 53: 25-28, 2010.
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[PubMed: 19887127]
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[Full Text: https://doi.org/10.1016/j.ejmg.2009.10.004]
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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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Mitchell, J., Punthakee, Z., Lo, B., Bernard, C., Chong, K., Newman, C., Cartier, L., Desilets, V., Cutz, E., Hansen, I. L., Riley, P., Polychronakos, C.
|
|
<strong>Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.</strong>
|
|
Diabetologia 47: 2160-2167, 2004.
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[PubMed: 15592663]
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[Full Text: https://doi.org/10.1007/s00125-004-1576-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Patel, K. A., Kettunen, J., Laakso, M., Stancakova, A., Laver, T. W., Colclough, K., Johnson, M. B., Abramowicz, M., Groop, L., Miettinen, P. J., Shepherd, M. H., Flanagan, S. E., Ellard, S., Inagaki, N., Hattersley, A. T., Tuomi, T., Cnop, M., Weedon, M. N.
|
|
<strong>Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.</strong>
|
|
Nature Commun. 8: 888, 2017.
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[PubMed: 29026101]
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[Full Text: https://doi.org/10.1038/s41467-017-00895-9]
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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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Sansbury, F. H., Kirel, B., Caswell, R., Allen, H. L., Flanagan, S. E., Hattersley, A. T., Ellard, S., Shaw-Smith, C. J.
|
|
<strong>Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus.</strong>
|
|
Europ. J. Hum. Genet. 23: 1744-1748, 2015. Note: Erratum: Europ. J. Hum. Genet. 23: 1750 only, 2015.
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[PubMed: 26264437]
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[Full Text: https://doi.org/10.1038/ejhg.2015.161]
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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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Smith, S. B., Qu, H.-Q., Taleb, N. Kishimoto, N. Y., Scheel, D. W., Lu, Y., Patch, A.-M., Grabs, R., Wang, J., Lynn, F. C., Miyatsuka, T., Mitchell, J., and 16 others.
|
|
<strong>Rfx6 directs islet formation and insulin production in mice and humans.</strong>
|
|
Nature 463: 775-780, 2010.
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[PubMed: 20148032]
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[Full Text: https://doi.org/10.1038/nature08748]
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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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Walker, J. T., Saunders, D. C., Rai, V., Chen, H.-H., Orchard, P., Dai, C., Pettway, Y. D., Hopkirk, A. L., Reihsmann, C. V., Tao, Y., Fan, S., Shrestha, S., and 21 others.
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<strong>Genetic risk converges on regulatory networks mediating early type 2 diabetes.</strong>
|
|
Nature 624: 621-629, 2023.
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[PubMed: 38049589]
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[Full Text: https://doi.org/10.1038/s41586-023-06693-2]
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</p>
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</li>
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</ol>
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Contributors:
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/20/2024<br>Ada Hamosh - updated : 01/24/2023<br>Marla J. F. O'Neill - updated : 03/07/2016<br>Ada Hamosh - updated : 11/18/2014<br>Marla J. F. O'Neill - updated : 4/9/2014<br>Marla J. F. O'Neill - updated : 3/4/2010<br>Ada Hamosh - updated : 3/2/2010
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<span class="mim-text-font">
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Dorothy S. Reilly : 3/12/2009
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carol : 11/22/2024<br>alopez : 03/20/2024<br>carol : 01/26/2023<br>alopez : 01/24/2023<br>carol : 03/07/2016<br>mcolton : 5/18/2015<br>alopez : 11/18/2014<br>carol : 4/10/2014<br>carol : 4/9/2014<br>carol : 4/9/2014<br>carol : 3/4/2010<br>terry : 3/2/2010<br>mgross : 11/23/2009<br>wwang : 3/12/2009
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To ensure long-term funding for the OMIM project, we have diversified
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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