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Entry
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- *184757 - NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1
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- OMIM
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<p>
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<span class="h4">*184757</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/184757">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div 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=ENSG00000136931;t=ENST00000373588" 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=2516" 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=184757" 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=ENSG00000136931;t=ENST00000373588" 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_004959" 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_004959" 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=184757" 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=01702&isoform_id=01702_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/NR5A1" 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/984541,2052388,2077920,3121738,20070193,21618439,44894133,119607997,216409744,325495523,325495571,444738453,1093289503" 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/Q13285" 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=2516" 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=ENSG00000136931;t=ENST00000373588" 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=NR5A1" 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=NR5A1" 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+2516" 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/NR5A1" 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:2516" 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/2516" 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=chr9&hgg_gene=ENST00000373588.9&hgg_start=124481236&hgg_end=124507399&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 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:7983" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=184757[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 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=184757[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://gnomad.broadinstitute.org/gene/ENSG00000136931" 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=NR5A1" 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=NR5A1" 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=NR5A1" 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=NR5A1&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/PA31764" 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:7983" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0001078.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1346833" 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/NR5A1#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:1346833" 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/2516/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002296/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2516" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003623;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-010504-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2516" 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=NR5A1&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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184757
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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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NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1
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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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FUSHI TARAZU FACTOR, DROSOPHILA, HOMOLOG 1; FTZF1; FTZ1<br />
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STEROIDOGENIC FACTOR 1; SF1<br />
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ADRENAL 4 BINDING PROTEIN; AD4BP<br />
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EMBRYONAL LTR-BINDING PROTEIN; ELP
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NR5A1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NR5A1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/9/489?start=-3&limit=10&highlight=489">9q33.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:124481236-124507399&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'})">9:124,481,236-124,507,399</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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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617480,612965,612964,612964,613957" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="5">
|
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<span class="mim-font">
|
|
<a href="/geneMap/9/489?start=-3&limit=10&highlight=489">
|
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9q33.3
|
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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">
|
|
46XX sex reversal 4
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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/617480"> 617480 </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 dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
46XY sex reversal 3
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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|
<a href="/entry/612965"> 612965 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Adrenocortical insufficiency
|
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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/612964"> 612964 </a>
|
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<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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<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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<p>NR5A1 is a transcription factor belonging to the nuclear receptor superfamily. It binds the core motif AGGTCA and regulates many genes involved in reproduction, steroidogenesis, and sexual differentiation (summary by <a href="#35" class="mim-tip-reference" title="Tremblay, J. J., Viger, R. S. <strong>A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4.</strong> J. Biol. Chem. 278: 42637-42642, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907682</a>] [<a href="https://doi.org/10.1074/jbc.M305485200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907682">Tremblay and Viger, 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907682" 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="#27" class="mim-tip-reference" title="Ninomiya, Y., Okada, M., Kotomura, N., Suzuki, K., Tsukiyama, T., Niwa, O. <strong>Genomic organization and isoforms of the mouse ELP gene.</strong> J. Biochem. 118: 380-389, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543574</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543574">Ninomiya et al. (1995)</a> cloned 4 splice variants of mouse Nr5a1, which they called Elp. The 4 variants, Elp1, Elp2, Elp3, and Ad4bp/Sf1, encode 3 isoforms, as Elp3 and Ad4bp/Sf1 have identical coding sequences but differ in their 5-prime noncoding regions. All isoforms contain a DNA-binding domain, a proline-rich region, and region II. Elp2 and Elp3/Ad4bp/Sfl also have region III, which is missing in Elp1. RT-PCR analysis showed complex expression of the variants in mouse tissues, with only embryonal carcinoma cells expression all 4 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8543574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Oba, K., Yanase, T., Nomura. M., Morohashi, K., Takayanagi, R., Nawata, H. <strong>Structural characterization of human Ad4bp (SF-1) gene.</strong> Biochem. Biophys. Res. Commun. 226: 261-267, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8806624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8806624</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8806624">Oba et al. (1996)</a> cloned the genomic DNA of the human SF1 gene, the mammalian homolog of Drosophila Ftzf1. They noted that the deduced amino acid sequence of human SF1 consists of 461 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8806624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By screening an embryonic adrenal gland cDNA library, <a href="#37" class="mim-tip-reference" title="Wong, M., Ramayya, M. S., Chrousos, G. P., Driggers, P. H., Parker, K. L. <strong>Cloning and sequence analysis of the human gene encoding steroidogenic factor 1.</strong> J. Molec. Endocr. 17: 139-147, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8938589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8938589</a>] [<a href="https://doi.org/10.1677/jme.0.0170139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8938589">Wong et al. (1996)</a> cloned human NR5A1, which they called SF1. The deduced 461-amino acid protein contains 2 N-terminal zinc finger DNA-binding domains, followed by an FTZF1 box, a hinge region, a ligand-binding domain, and a C-terminal AF2 transactivation domain. SF2 also has an evolutionarily conserved consensus phosphorylation motif. Human SF2 shares 93 to 95% amino acid identity with cow, rat, and mouse Sf2. The authors noted that mouse Sf2 is alternatively spliced to produce 4 distinct transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8938589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemistry in rats to analyze NR5A1 expression during steroidogenesis and spermatogenesis, <a href="#18" class="mim-tip-reference" title="Kojima, Y., Sasaki, S., Hayashi, Y., Umemoto, Y., Morohashi, K.-I., Kohri, K. <strong>Role of transcription factors Ad4BP/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia.</strong> Int. J. Urol. 13: 785-793, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16834661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16834661</a>] [<a href="https://doi.org/10.1111/j.1442-2042.2006.01403.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16834661">Kojima et al. (2006)</a> observed expression in both Leydig and Sertoli cells in the 7-day-old rat, but expression levels decreased in Sertoli cells by 21 days, and was present only in Leydig cells in the 56-day-old sexually mature rat. In humans, quantitative RT-PCR and Western blot analysis of testicular tissue obtained from males at ages ranging from 1 year to 26 years showed increased expression with increasing age during testicular development. Expression patterns were similar to those seen in rats, with NR5A1 expressed in both Sertoli and Leydig cells in a 1-year-old boy, but showing decreased expression in Sertoli cells in an 8-year-old boy. In pubertal and adult testes NR5A1 was abundantly expressed in the nuclei of Leydig cells, with only a few Sertoli cells showing faint expression. <a href="#18" class="mim-tip-reference" title="Kojima, Y., Sasaki, S., Hayashi, Y., Umemoto, Y., Morohashi, K.-I., Kohri, K. <strong>Role of transcription factors Ad4BP/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia.</strong> Int. J. Urol. 13: 785-793, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16834661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16834661</a>] [<a href="https://doi.org/10.1111/j.1442-2042.2006.01403.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16834661">Kojima et al. (2006)</a> concluded that expression of NR5A1 is developmentally regulated, with maximal expression during puberty and high expression after puberty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16834661" 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="#28" class="mim-tip-reference" title="Oba, K., Yanase, T., Nomura. M., Morohashi, K., Takayanagi, R., Nawata, H. <strong>Structural characterization of human Ad4bp (SF-1) gene.</strong> Biochem. Biophys. Res. Commun. 226: 261-267, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8806624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8806624</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8806624">Oba et al. (1996)</a> determined that the human SF1 gene spans 30 kb of genomic DNA and is split into 7 exons, including the noncoding first exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8806624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Wong, M., Ramayya, M. S., Chrousos, G. P., Driggers, P. H., Parker, K. L. <strong>Cloning and sequence analysis of the human gene encoding steroidogenic factor 1.</strong> J. Molec. Endocr. 17: 139-147, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8938589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8938589</a>] [<a href="https://doi.org/10.1677/jme.0.0170139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8938589">Wong et al. (1996)</a> determined that the NR5A1 gene contains 7 exons and spans 22 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8938589" 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="#33" class="mim-tip-reference" title="Taketo, M., Parker, K. L., Howard, T. A., Tsukiyama, T., Wong, M., Niwa, O., Morton, C. C., Miron, P. M., Seldin, M. F. <strong>Homologs of Drosophila fushi-tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33.</strong> Genomics 25: 565-567, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789992</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80059-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789992">Taketo et al. (1995)</a> mapped the human NR5A1 gene to chromosome 9q33 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7789992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By linkage analysis using interspecific backcross mice, <a href="#32" class="mim-tip-reference" title="Swift, S., Ashworth, A. <strong>The mouse Ftzf1 gene required for gonadal and adrenal development maps to mouse chromosome 2.</strong> Genomics 28: 609-610, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7490110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7490110</a>] [<a href="https://doi.org/10.1006/geno.1995.1204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7490110">Swift and Ashworth (1995)</a> mapped the Nr5a1 gene to mouse chromosome 2. <a href="#33" class="mim-tip-reference" title="Taketo, M., Parker, K. L., Howard, T. A., Tsukiyama, T., Wong, M., Niwa, O., Morton, C. C., Miron, P. M., Seldin, M. F. <strong>Homologs of Drosophila fushi-tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33.</strong> Genomics 25: 565-567, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789992</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80059-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789992">Taketo et al. (1995)</a> further mapped the mouse gene to the proximal quarter of the chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7789992+7490110" 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="#23" class="mim-tip-reference" title="Luo, X., Ikeda, Y., Parker, K. L. <strong>A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation.</strong> Cell 77: 481-490, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8187173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8187173</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90211-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8187173">Luo et al. (1994)</a> reviewed studies implicating SF1 in gonadal differentiation and steroidogenesis. Studies in adrenocortical cells implicated an orphan nuclear receptor, alternatively designated steroidogenic factor-1 (SF1) or adrenal 4-binding protein (AD4BP), in the gene regulation of the 3 enzymes that are required for the biosynthesis of corticosteroids: cholesterol side chain cleavage enzyme (CYP11A1; <a href="/entry/118485">118485</a>), steroid 21-hydroxylase (CYP21A2; <a href="/entry/613815">613815</a>), and the aldosterone synthase isozyme of steroid 11-beta-hydroxylase (CYP11B2; <a href="/entry/124080">124080</a>). Consistent with this postulated role, SF1 in adult mice is expressed in all primary steroidogenic tissues, including the adrenal cortex, testicular Leydig cells, and ovarian theca and granulosa cells and corpus luteum. Furthermore, it is expressed in the urogenital ridge of mouse embryos at embryonic day 9-9.5, the earliest stage of organogenesis of the developing gonads, and is also expressed in fetal Sertoli cells. Structural analysis of an SF1 cDNA showed that it closely matches a mouse cDNA isolated from an embryonal carcinoma cell cDNA library and designated embryonal long terminal repeat-binding protein (ELP) because it binds regulatory elements in retroviral long terminal repeats. Isolation and characterization of genomic clones demonstrated that both SF1 and ELP arose from the same structural gene by alternative promoter usage and splicing. Especially in their shared zinc finger DNA-binding domains, SF1 and ELP closely resembled an orphan nuclear receptor isolated from Drosophila, designated fushi tarazu factor-1, or FTZ-F1 (<a href="#19" class="mim-tip-reference" title="Lala, D. S., Rice, D. A., Parker, K. L. <strong>Steroidogenic factor 1, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor 1.</strong> Molec. Endocr. 6: 1249-1258, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1406703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1406703</a>] [<a href="https://doi.org/10.1210/mend.6.8.1406703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1406703">Lala et al., 1992</a>). For that reason, the mouse gene was designated Ftz-F1. The homologous gene in Drosophila also encodes 2 distinct transcripts proposed to play important roles in Drosophila development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8187173+1406703" 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="#30" class="mim-tip-reference" title="Shen, W.-H., Moore, C. C. D., Ikeda, Y., Parker, K. L., Ingraham, H. A. <strong>Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: a link to the sex determination cascade.</strong> Cell 77: 651-661, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8205615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8205615</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90050-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8205615">Shen et al. (1994)</a> proposed that SF1 regulates MIS (<a href="/entry/600957">600957</a>) in vivo and participates directly in the process of mammalian sex determination. This conclusion was based on several observations. First, in primary Sertoli cells, SF1 regulates the MIS gene by binding to a conserved upstream regulatory element. Second, in heterologous (HeLa) cells, MIS gene activation by SF1 requires removal of the SF1 ligand-binding domain, implicating a Sertoli cell-specific ligand or cofactor. Finally, the sexually dimorphic expression of SF1 during development coincides with MIS expression and mullerian duct regression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8205615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transfected NIH3T3 cells, <a href="#27" class="mim-tip-reference" title="Ninomiya, Y., Okada, M., Kotomura, N., Suzuki, K., Tsukiyama, T., Niwa, O. <strong>Genomic organization and isoforms of the mouse ELP gene.</strong> J. Biochem. 118: 380-389, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8543574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8543574</a>] [<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8543574">Ninomiya et al. (1995)</a> showed that mouse Elp1 functioned as a transcription repressor, whereas the other Elp isoforms functioned as transactivators. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8543574" 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="#26" class="mim-tip-reference" title="Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Flanagan, J. N., Hammer, G. D., Ingraham, H. A. <strong>Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.</strong> Cell 93: 445-454, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590178">Nachtigal et al. (1998)</a> showed that WT1(-KTS) (<a href="/entry/607102">607102</a>) isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (<a href="/entry/194080">194080</a>), fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; <a href="/entry/300018">300018</a>) gene, DAX1 (NR0B1; <a href="/entry/300473">300473</a>), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. <a href="#26" class="mim-tip-reference" title="Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Flanagan, J. N., Hammer, G. D., Ingraham, H. A. <strong>Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.</strong> Cell 93: 445-454, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590178">Nachtigal et al. (1998)</a> proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590178" 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 determine the molecular mechanisms underlying transcriptional regulation of SF1 gene expression in the pituitary, <a href="#14" class="mim-tip-reference" title="Harris, A. N., Mellon, P. L. <strong>The basic helix-loop-helix, leucine zipper transcription factor, USF (upstream stimulatory factor), is a key regulator of SF-1 (steroidogenic factor-1) gene expression in pituitary gonadotrope and steroidogenic cells.</strong> Molec. Endocr. 12: 714-726, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605934</a>] [<a href="https://doi.org/10.1210/mend.12.5.0100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9605934">Harris and Mellon (1998)</a> studied a series of deletion and point mutations in the SF1 promoter region for transcriptional activity in alpha-T3-1 and L-beta-T2 (pituitary gonadotrope), CV-1, JEG-3, and Y1 (adrenocortical) cell lines. Their results indicated that maximal expression of the SF1 promoter in all cell types requires an E box element at -82/-77. This E box sequence (CACGTG) is identical to the binding element for upstream stimulatory factor-1 (USF1; <a href="/entry/191523">191523</a>), a member of the helix-loop-helix family of transcription factors. Studies of the SF1 gene E box element using gel mobility shift and antibody supershift assays indicated that USF1 may be a key transcriptional regulator of SF1 gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605934" 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="#13" class="mim-tip-reference" title="Hammer, G. D., Krylova, I., Zhang, Y., Darimont, B. D., Simpson, K., Weigel, N. L., Ingraham, H. A. <strong>Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress.</strong> Molec. Cell 3: 521-526, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10230405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10230405</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80480-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10230405">Hammer et al. (1999)</a> demonstrated that maximal SF1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (ser-203) located in a major activation domain (AF1) of the protein. Moreover, phosphorylation-dependent SF1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway (see <a href="/entry/603014">603014</a>). They proposed that this single modification of SF1 and the subsequent recruitment of nuclear receptor cofactors couple extracellular signals to steroid and peptide hormone synthesis, thereby maintaining dynamic homeostatic responses in stress and reproduction. <a href="#34" class="mim-tip-reference" title="Tremblay, A., Tremblay, G. B., Labrie, F., Giguere, V. <strong>Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1.</strong> Molec. Cell 3: 513-519, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10230404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10230404</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80479-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10230404">Tremblay et al. (1999)</a> demonstrated that phosphorylation of AF1 by MAPK leads to the recruitment of steroid receptor coactivator-1 (<a href="/entry/602691">602691</a>) by estrogen receptor-beta (<a href="/entry/601663">601663</a>) in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10230405+10230404" 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="#25" class="mim-tip-reference" title="Morohashi, K. <strong>Gonadal and extragonadal functions of Ad4BP/SF-1: developmental aspects.</strong> Trends Endocr. Metab. 10: 169-173, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10370224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10370224</a>] [<a href="https://doi.org/10.1016/s1043-2760(98)00142-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10370224">Morohashi (1999)</a> reviewed the gonadal and extragonadal functions of AD4BP/SF1, focusing on the developmental aspects. Gene disruption studies had shown that AD4BP/SF1, originally identified as a steroidogenic tissue-specific transcription factor, plays crucial roles in the process of nonsteroidogenic as well as steroidogenic tissue differentiation. Although the mechanisms underlying differentiation of these tissues were still under investigation, spatial and temporal expression profiles of the AD4BP/SF1 gene supported its contribution to tissue development from the earliest stages of ontogeny. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10370224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Gizard, F., Lavallee, B., DeWitte, F., Teissier, E., Staels, B., Hum, D. W. <strong>The transcriptional regulating protein of 132 kDa (TReP-132) enhances P450scc gene transcription through interaction with steroidogenic factor-1 in human adrenal cells.</strong> J. Biol. Chem. 277: 39144-39155, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12101186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12101186</a>] [<a href="https://doi.org/10.1074/jbc.M205786200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12101186">Gizard et al. (2002)</a> found that coexpression of SF1 and TREP132 (TRERF1; <a href="/entry/610322">610322</a>) in an adrenal carcinoma cell line increased CYP11A1 promoter activity, and pull-down, 2-hybrid, and coimmunoprecipitation analyses confirmed SF1-TREP132 interaction. Deletion and mutation analysis showed that the proximal activation domain and AF2 hexamer motif of SF1 interacted with the LxxLL motif in the N-terminal region of TREP132. Coexpression of CBP (CREBBP; <a href="/entry/600140">600140</a>)/p300 (EP300; <a href="/entry/602700">602700</a>) with SF1 and TREP132 resulted in a synergistic effect on CYP11A1 promoter activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12101186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Xue, Q., Lin, Z., Yin, P., Milad, M. P., Cheng, Y.-H., Confino, E., Reierstad, S., Bulun, S. E. <strong>Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5-prime CpG island in endometriosis.</strong> J. Clin. Endocr. Metab. 92: 3261-3267, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17519303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17519303</a>] [<a href="https://doi.org/10.1210/jc.2007-0494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17519303">Xue et al. (2007)</a> identified a CpG island flanking the SF1 promoter and exon I region (-85/+239) and determined its methylation patterns in endometrial and endometriotic cells. SF1 mRNA and protein levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells (p less than 0.001). Bisulfite sequencing showed strikingly increased methylation in endometrial cells, compared with endometriotic cells (p less than 0.001). <a href="#38" class="mim-tip-reference" title="Xue, Q., Lin, Z., Yin, P., Milad, M. P., Cheng, Y.-H., Confino, E., Reierstad, S., Bulun, S. E. <strong>Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5-prime CpG island in endometriosis.</strong> J. Clin. Endocr. Metab. 92: 3261-3267, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17519303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17519303</a>] [<a href="https://doi.org/10.1210/jc.2007-0494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17519303">Xue et al. (2007)</a> concluded that this was the first demonstration of methylation-dependent regulation of SF1 in any mammalian tissue and suggested that these findings pointed to a new mechanism for targeting local estrogen biosynthesis in endometriosis (<a href="/entry/131200">131200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17519303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> demonstrated that SRY (<a href="/entry/480000">480000</a>) binds to multiple elements within a Sox9 (<a href="/entry/608160">608160</a>) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with SF1. Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. <a href="#29" class="mim-tip-reference" title="Sekido, R., Lovell-Badge, R. <strong>Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.</strong> Nature 453: 930-934, 2008. Note: Erratum: Nature 456: 824 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18454134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18454134</a>] [<a href="https://doi.org/10.1038/nature06944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18454134">Sekido and Lovell-Badge (2008)</a> concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18454134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Kojima, Y., Sasaki, S., Hayashi, Y., Umemoto, Y., Morohashi, K.-I., Kohri, K. <strong>Role of transcription factors Ad4BP/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia.</strong> Int. J. Urol. 13: 785-793, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16834661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16834661</a>] [<a href="https://doi.org/10.1111/j.1442-2042.2006.01403.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16834661">Kojima et al. (2006)</a> analyzed expression levels of NR5A1 mRNA in testicular tissue from 22 patients with nonobstructive azoospermia, and detected NR5A1 in all specimens. Quantitative RT-PCR showed a significant positive correlation between the expression level of NR5A1 and serum testosterone concentration; however, there was no correlation with the severity of histologic pathology observed in the testicular tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16834661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., Buonocore, F., Barseghyan, H., Bingham, N., Rosenfeld, J. A., Mulukutla, S. N., Jain, M., and 25 others. <strong>A recurrent p.arg92trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.</strong> Hum. Molec. Genet. 25: 3446-3453, 2016. Note: Erratum: Hum. Molec. Genet. 25: 5286 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27378692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27378692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27378692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27378692">Bashamboo et al. (2016)</a> found that in contrast to mouse, where nr5a1 is expressed specifically in the somatic cells of the testis and only trace expression is seen in the early ovary, in human embryos expression of NR5A1 is similar in ovary and testis and higher than in other tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27378692" 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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Steroidogenic factor-1 is an orphan nuclear receptor that regulates the transcription of an array of genes involved in reproduction, steroidogenesis, and male sexual differentiation, including AMH (<a href="/entry/600957">600957</a>), DAX1, CYP11A1, steroidogenic acute regulatory protein (STAR; <a href="/entry/600617">600617</a>), and those encoding steroid hydroxylases, gonadotropins, and aromatase. Disruption of the Ftzf1 gene in mice causes failure of adrenal and gonadal development, XY sex reversal, persistence of mullerian structures in males, and abnormalities of the hypothalamus and pituitary gonadotropes (see later). In a phenotypically female patient who presented with primary adrenal failure in the first 2 weeks of life and had a 46,XY karyotype (SRXY3; <a href="/entry/612965">612965</a>), <a href="#1" class="mim-tip-reference" title="Achermann, J. C., Ito, M., Ito, M., Hindmarsh, P. C., Jameson, J. L. <strong>A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. (Letter)</strong> Nature Genet. 22: 125-126, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369247</a>] [<a href="https://doi.org/10.1038/9629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369247">Achermann et al. (1999)</a> identified heterozygosity for a 2-bp mutation in exon 3 (<a href="#0001">184757.0001</a>) of the SF1 gene, which encodes part of the DNA-binding domain. By site-directed mutagenesis, <a href="#1" class="mim-tip-reference" title="Achermann, J. C., Ito, M., Ito, M., Hindmarsh, P. C., Jameson, J. L. <strong>A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. (Letter)</strong> Nature Genet. 22: 125-126, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369247</a>] [<a href="https://doi.org/10.1038/9629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369247">Achermann et al. (1999)</a> created the G35E mutant form of SF1 for use in functional studies. The mutation did not interfere with protein translation, stability, or nuclear localization, but it eliminated the binding of SF1 to a canonical binding site. Consistent with its impaired DNA binding, the G35E SF1 mutant did not transactivate a known SF1-responsive reporter gene. The mutant SF1 did not exhibit dominant-negative activity when coexpressed with wildtype SF1. The SF1 mutation in this patient caused complete XY sex reversal, including normal female external genitalia and retention of the uterus. This contrasts with disorders of steroid biosynthesis, in which no uterus is present. The findings provided evidence that SF1 regulates the regression of mullerian structures in humans, either through direct actions on AMH or secondary to an abnormality of Sertoli cell development or function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369247" 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="#20" class="mim-tip-reference" title="Lin, L., Gu, W.-X., Ozisik, G., To, W. S., Owen, C. J., Jameson, J. L., Achermann, J. C. <strong>Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.</strong> J. Clin. Endocr. Metab. 91: 3048-3054, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684822[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/10.1210/jc.2006-0603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684822">Lin et al. (2006)</a> studied the prevalence of DAX1 and SF1 mutations in 117 children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). SF1 mutations causing adrenal failure were found in only 2 patients with 46,XY gonadal dysgenesis. <a href="#20" class="mim-tip-reference" title="Lin, L., Gu, W.-X., Ozisik, G., To, W. S., Owen, C. J., Jameson, J. L., Achermann, J. C. <strong>Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: ten years' experience.</strong> J. Clin. Endocr. Metab. 91: 3048-3054, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684822</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684822[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/10.1210/jc.2006-0603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684822">Lin et al. (2006)</a> concluded that SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684822" 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="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> analyzed the NR5A1 gene in 30 patients with 46,XY disorders of sex development and identified heterozygous missense mutations in 4 patients (<a href="#0007">184757.0007</a>-<a href="#0010">184757.0010</a>, respectively). Three of the mutations showed loss of function in adrenal, Leydig, and Sertoli cells lines, but an L437Q ligand-binding domain mutant identified in 1 of the patients (<a href="#0010">184757.0010</a>) retained partial activity in these cell systems, consistent with the milder clinical phenotype of that patient (hypospadias, male gender assignment). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200175" 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="#17" class="mim-tip-reference" title="Kohler, B., Lin, L., Ferraz-de-Souza, B., Wieacker, P., Heidemann, P., Schroder, V., Biebermann, H., Schnabel, D., Gruters, A., Achermann, J. C. <strong>Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency.</strong> Hum. Mutat. 29: 59-64, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17694559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17694559</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17694559[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/10.1002/humu.20588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17694559">Kohler et al. (2008)</a> analyzed the NR5A1 gene in 27 German 46,XY patients with severe underandrogenization without adrenal insufficiency and identified heterozygous mutations in 5 (18.5%) patients; the authors concluded that NR5A1 mutations are a relatively frequent cause of 46,XY disorders of sex development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17694559" 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>NR5A1-Related Adrenal Insufficiency</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Biason-Lauber, A., Schoenle, E. J. <strong>Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency.</strong> Am. J. Hum. Genet. 67: 1563-1568, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11038323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11038323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11038323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11038323">Biason-Lauber and Schoenle (2000)</a> described a female patient with adrenal insufficiency and no apparent defect in ovarian maturation (see <a href="/entry/612964">612964</a>), despite a heterozygous mutation in the NR5A1 gene (<a href="#0002">184757.0002</a>). The authors concluded that NR5A1 has a crucial role in adrenal gland formation in both sexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11038323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Guran, T., Buonocore, F., Saka, N., Ozbek, M. N., Aycan, Z., Bereket, A., Bas, F., Darcan, S., Bideci, A., Guven, A., Demir, K., Akinci, A., and 21 others. <strong>Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort.</strong> J. Clin. Endocr. Metab. 101: 284-292, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26523528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26523528</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26523528[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/10.1210/jc.2015-3250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26523528">Guran et al. (2016)</a> described a 2-week-old girl with primary adrenal insufficiency, 46,XX karyotype, normal female phenotype, and no evidence of ovarian insufficiency. She carried a homozygous arg92-to-gln mutation in NR5A1 (R92Q; <a href="#0003">184757.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26523528" 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>Adrenocortical Tumors</em></strong></p><p>
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Using comparative genomic hybridization, <a href="#10" class="mim-tip-reference" title="Figueiredo, B. C., Cavalli, L. R., Pianovski, M. A. D., Lalli, E., Sandrini, R., Ribeiro, R. C., Zambetti, G., DeLacerda, L., Rodrigues, G. A., Haddad, B. R. <strong>Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors.</strong> J. Clin. Endocr. Metab. 90: 615-619, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15546904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15546904</a>] [<a href="https://doi.org/10.1210/jc.2004-0942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15546904">Figueiredo et al. (2005)</a> detected a consistent gain of chromosome 9q or a portion of it in 8 of 9 cases of pediatric adrenocortical tumors (ACTs) and amplification of 9q34 in the majority of these cases. They also examined if the SF1 gene, which is located in this chromosomal region and plays an important role in the development and function of the adrenal cortex, is amplified in these ACT cases. They detected increased copy number of the SF1 gene in all 8 cases with 9q gain, suggesting an association between an increased copy number of the SF1 gene and adrenocortical tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15546904" 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>Premature Ovarian Failure 7</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> sequenced the NR5A1 gene in 4 families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. They identified mutations in patients with premature ovarian failure (POF7; <a href="/entry/612964">612964</a>) as well as in patients with 46,XY disorders (<a href="#0011">184757.0011</a>-<a href="#0016">184757.0016</a>). None of the affected subjects had clinical signs of adrenal insufficiency. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. None of the mutations were observed in more than 700 control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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>Spermatogenic Failure 8</em></strong></p><p>
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<a href="#5" class="mim-tip-reference" title="Bashamboo, A., Ferraz-de-Souza, B., Lourenco, D., Lin, L., Sebire, N. J., Montjean, D., Bignon-Topalovic, J., Mandelbaum, J., Siffroi, J.-P., Christin-Maitre, S., Radhakrishna, U., Rouba, H., Ravel, C., Seeler, J., Achermann, J. C., McElreavey, K. <strong>Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.</strong> Am. J. Hum. Genet. 87: 505-512, 2010. Note: Erratum. Am. J. Hum. Genet. 87: 736 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20887963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20887963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20887963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20887963">Bashamboo et al. (2010)</a> analyzed the candidate gene NR5A1 in 315 men with idiopathic spermatogenic failure and identified heterozygous missense mutations in 7 of them (see, e.g., <a href="#0016">184757.0016</a>-<a href="#0018">184757.0018</a>). This form of the disorder is designated spermatogenic failure-8 (SPGF8; <a href="/entry/613957">613957</a>). None of the mutations were found in more than 2,100 control samples, and analysis of the entire coding region of NR5A1 in 370 fertile men (father of at least 2 children) or 359 normospermic men revealed no rare allelic variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20887963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>46,XX Sex Reversal 4</em></strong></p><p>
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Using whole-exome, whole-genome, or direct sequencing, <a href="#4" class="mim-tip-reference" title="Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., Buonocore, F., Barseghyan, H., Bingham, N., Rosenfeld, J. A., Mulukutla, S. N., Jain, M., and 25 others. <strong>A recurrent p.arg92trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.</strong> Hum. Molec. Genet. 25: 3446-3453, 2016. Note: Erratum: Hum. Molec. Genet. 25: 5286 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27378692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27378692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27378692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27378692">Bashamboo et al. (2016)</a> showed that a specific recurrent heterozygous missense mutation, arg92-to-trp (R92W; <a href="#0019">184757.0019</a>), in the accessory DNA-binding region of NR5A1 was associated with a variable degree of testis development in 46,XX children and adults from 4 unrelated families (SRXX4; <a href="/entry/617480">617480</a>). Remarkably, in 1 family a sib of the proband, raised as a girl and carrying this NR5A1 mutation, was found to have a 46,XY karyotype and partial testicular dysgenesis (SRXY3; <a href="/entry/612965">612965</a>). <a href="#4" class="mim-tip-reference" title="Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., Buonocore, F., Barseghyan, H., Bingham, N., Rosenfeld, J. A., Mulukutla, S. N., Jain, M., and 25 others. <strong>A recurrent p.arg92trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.</strong> Hum. Molec. Genet. 25: 3446-3453, 2016. Note: Erratum: Hum. Molec. Genet. 25: 5286 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27378692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27378692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27378692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27378692">Bashamboo et al. (2016)</a> concluded that these findings highlighted how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals, and represented the first missense mutation causing isolated, nonsyndromic 46,XX testicular/ovotesticular DSD in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27378692" 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="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a> screened a cohort of 11 unrelated cases and 2 sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD) using whole-exome sequencing in 9 patients, targeted resequencing in 4, and haplotyping. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. <a href="#3" class="mim-tip-reference" title="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a> identified a novel heterozygous NR5A1 mutation, c.274C-T (arg92 to trp, R92W; <a href="#0019">184757.0019</a>), in 3 unrelated patients. The arg92 residue is highly conserved and located in the Ftz-F1 region, which is thought to be involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1 (<a href="/entry/300120">300120</a>), a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 (<a href="/entry/605597">605597</a>) and testicular SRY (<a href="/entry/480000">480000</a>)-independent SOX9 (<a href="/entry/608160">608160</a>) expression was observed. <a href="#3" class="mim-tip-reference" title="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a> proposed NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD and hypothesized that the R92W mutation results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. <a href="#3" class="mim-tip-reference" title="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a> concluded that their study supported a role for NR5A1 in testis differentiation in the XX gonad. In the first family reported by <a href="#3" class="mim-tip-reference" title="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a>, the proband's healthy sister, father, paternal uncle and grandfather all carried the R92W mutation in NR5A1. A younger sister of the second proband carried the same mutation and displayed normal puberty. In the third family, the proband's 2 younger brothers and mother, all unaffected, carried the R92W mutation. All affected mutation carriers shared a common haplotype spanning a 1.5-Mb region. No other known variants associated with 46,XX sex reversal were identified in any of the probands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27490115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 46,XX patient with bilateral ovotestes, <a href="#31" class="mim-tip-reference" title="Swartz, J. M., Ciarlo, R., Guo, M. H., Abrha, A., Weaver, B., Diamond, D. A., Chan, Y.-M., Hirschhorn, J. N. <strong>A 46,XX ovotesticular disorder of sex development likely caused by a steroidogenic factor-1 (NR5A1) variant.</strong> Horm. Res. Paediat. 87: 191-195, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27855412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27855412</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27855412[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/10.1159/000452888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27855412">Swartz et al. (2017)</a> identified a heterozygous arg92-to-gln (R92Q; <a href="#0003">184757.0003</a>) mutation, inherited from the unaffected father. This mutation had previously been reported in a patient with 46,XY DSD (SRXY3; <a href="/entry/612965">612965</a>) and in a 46,XX infant with normal female phenotype and adrenal insufficiency (see <a href="/entry/612964">612964</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27855412" 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>Exclusion Studies</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Calvo, R. M., Asuncion, M., Telleria, D., Sancho, J., San Millan, J. L., Escobar-Morreale, H. F. <strong>Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women.</strong> J. Clin. Endocr. Metab. 86: 1746-1749, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297612</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297612">Calvo et al. (2001)</a> used heteroduplex analysis to screen the genes encoding STAR, SF1, DAX1, and CYP11A1 for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. Two variants in the SF1 gene were identified. The authors concluded that mutations in STAR, SF1, CYP11A1, and DAX1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities found in these women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297612" 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>To examine the role of Ftzf1 in intact mice, <a href="#23" class="mim-tip-reference" title="Luo, X., Ikeda, Y., Parker, K. L. <strong>A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation.</strong> Cell 77: 481-490, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8187173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8187173</a>] [<a href="https://doi.org/10.1016/0092-8674(94)90211-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8187173">Luo et al. (1994)</a> used targeted disruption of the Ftzf1 gene. Despite normal survival in utero, all Ftzf1-null animals died by postnatal day 8; these animals lacked adrenal glands and gonads and were severely deficient in corticosterone, supporting adrenocortical insufficiency as the probable cause of death. Male and female Ftzf1-null mice had female internal genitalia, despite complete gonadal agenesis. These studies established that the Ftzf1 gene is essential for sexual differentiation and formation of the primary steroidogenic tissues. Normal male sex differentiation requires that Sertoli cells in the embryonic testes produce mullerian-inhibiting substance (AMH; <a href="/entry/600957">600957</a>), a TGF-beta-like hormone that causes mullerian duct regression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8187173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Because of the demonstration that reduced expression of steroidogenic factor-1 in patients leads to adrenal failure, <a href="#7" class="mim-tip-reference" title="Bland, M. L., Jamieson, C. A. M., Akana, S. F., Bornstein, S. R., Eisenhofer, G., Dallman, M. F., Ingraham, H. A. <strong>Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response.</strong> Proc. Nat. Acad. Sci. 97: 14488-14493, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11121051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11121051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11121051[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.26.14488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11121051">Bland et al. (2000)</a> examined SF1 heterozygous mice as a potential model for delineating the mechanisms underlying this disorder. They showed that SF1 +/- mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein (<a href="/entry/600617">600617</a>), help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF1 heterozygotes were revealed under stressful conditions, demonstrating that normal gene dosage of SF1 is required for mounting an adequate stress response. The findings predicted that natural variations leading to reduced SF1 function may underlie some forms of subclinical adrenal insufficiency that become life-threatening during traumatic stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11121051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transgenic mice, <a href="#36" class="mim-tip-reference" title="Wilhelm, D., Englert, C. <strong>The Wilms tumor suppressor WT1 regulates early gonadal development by activation of Sf1.</strong> Genes Dev. 16: 1839-1851, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12130543[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.220102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130543">Wilhelm and Englert (2002)</a> showed that Wt1(-KTS) binds to 4 promoter sequences of the Sf1 gene, and that Wt1(-KTS) and Lhx9 (<a href="/entry/606066">606066</a>) have an additive effect in activating the Sf1 promoter. Wt1 was also shown to regulate Dax1 activity in vivo. Gonad development and Dax1 and Sf1 expression were absent in Wt1 mutant mouse embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130543" 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>As the cause of XY sex reversal and adrenal failure in a phenotypically female patient (SRXY3; <a href="/entry/612965">612965</a>), <a href="#1" class="mim-tip-reference" title="Achermann, J. C., Ito, M., Ito, M., Hindmarsh, P. C., Jameson, J. L. <strong>A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. (Letter)</strong> Nature Genet. 22: 125-126, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369247</a>] [<a href="https://doi.org/10.1038/9629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369247">Achermann et al. (1999)</a> found a heterozygous 2-bp GGC-to-GAA (glycine-to-glutamic acid; G35E) mutation in exon 3 of the NR5A1 gene. The mutated glycine is the last amino acid in the proximal box (P-box) of the first zinc finger of SF1. This region is critical for the recognition of DNA binding sites and confers specificity to nuclear receptors in the regulation of target genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse and rat constructs, <a href="#35" class="mim-tip-reference" title="Tremblay, J. J., Viger, R. S. <strong>A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4.</strong> J. Biol. Chem. 278: 42637-42642, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907682</a>] [<a href="https://doi.org/10.1074/jbc.M305485200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907682">Tremblay and Viger (2003)</a> found that the SF1 G35E mutant bound the promoter region of the MIS gene (AMH; <a href="/entry/600957">600957</a>) and interacted normally with its protein coactivator, GATA4 (<a href="/entry/600576">600576</a>), but that it failed to cooperate with GATA4 to activate the MIS reporter gene. Moreover, SF1 G35E functioned as a dominant-negative competitor and disrupted transcriptional synergism between wildtype SF1 and GATA4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907682" 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> rs104894118 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894118;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/rs104894118?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=rs104894118" 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=rs104894118" 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=RCV000013639" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013639" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013639</a>
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<p><a href="#6" class="mim-tip-reference" title="Biason-Lauber, A., Schoenle, E. J. <strong>Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency.</strong> Am. J. Hum. Genet. 67: 1563-1568, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11038323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11038323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11038323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/316893" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11038323">Biason-Lauber and Schoenle (2000)</a> described a phenotypically normal girl who presented at age 14 months with adrenal insufficiency and no apparent defect in ovarian maturation (see <a href="/entry/612964">612964</a>). The authors identified a heterozygous G-to-T transversion in exon 4 of the NR5A1 gene, leading to an arg255-to-leu (R255L) mutation in the hinge region of the NR5A1 protein. There was no evidence of mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11038323" 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 46,XY SEX REVERSAL 3</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">rs104894119 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894119;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=rs104894119" 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=rs104894119" 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=RCV000013640 OR RCV000490544 OR RCV000490549" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013640, RCV000490544, RCV000490549" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013640...</a>
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<p><strong><em>46,XY Sex Reversal 3</em></strong></p><p>
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In an infant with adrenal failure and complete 46,XY sex reversal (SRXY3; <a href="/entry/612965">612965</a>), <a href="#2" class="mim-tip-reference" title="Achermann, J. C., Ozisik, G., Ito, M., Orun, U. A., Harmanci, K., Gurakan, B., Jameson, J. L. <strong>Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner.</strong> J. Clin. Endocr. Metab. 87: 1829-1833, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932325</a>] [<a href="https://doi.org/10.1210/jcem.87.4.8376" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932325">Achermann et al. (2002)</a> reported a homozygous G-to-A transition in exon 4 of the NR5A1 gene, which resulted in an arg92-to-gln (R92Q) amino acid change. This mutation altered a highly conserved residue of the A box, a region that functions as a secondary DNA binding domain. Three relatives of the infant (parents and a sister) were phenotypically normal despite being heterozygous for the mutation. In functional assays, the R92Q mutant exhibited partial loss of DNA binding and transcriptional activity when compared with the G35E P-box change (<a href="#0001">184757.0001</a>), consistent with its phenotypic expression only when transmitted as a homozygous trait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>46,XX Sex Reversal 4</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Swartz, J. M., Ciarlo, R., Guo, M. H., Abrha, A., Weaver, B., Diamond, D. A., Chan, Y.-M., Hirschhorn, J. N. <strong>A 46,XX ovotesticular disorder of sex development likely caused by a steroidogenic factor-1 (NR5A1) variant.</strong> Horm. Res. Paediat. 87: 191-195, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27855412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27855412</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27855412[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/10.1159/000452888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27855412">Swartz et al. (2017)</a> reported a 46,XX individual of European ancestry with ambiguous genitalia, including significant clitoromegaly and rugated labia majora (SRXX4; <a href="/entry/617480">617480</a>). Ultrasound and MRI showed a small uterus and abdominal gonads that were revealed to be ovotestes bilaterally by histologic analysis. The patient carried a heterozygous R92Q mutation, inherited from her unaffected father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27855412" 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>NR5A1-related Adrenal Insufficiency</em></strong></p><p>
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In a 2-week-old girl with primary adrenal insufficiency (see <a href="/entry/612964">612964</a>) who presented with hyperpigmentation, salt-wasting crisis, prolonged jaundice, hypoglycemia, and vomiting, <a href="#12" class="mim-tip-reference" title="Guran, T., Buonocore, F., Saka, N., Ozbek, M. N., Aycan, Z., Bereket, A., Bas, F., Darcan, S., Bideci, A., Guven, A., Demir, K., Akinci, A., and 21 others. <strong>Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large nationwide cohort.</strong> J. Clin. Endocr. Metab. 101: 284-292, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26523528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26523528</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26523528[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/10.1210/jc.2015-3250" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26523528">Guran et al. (2016)</a> detected homozygosity for a R92Q substitution in NR5A1. The karyotype was 46,XX with a normal female phenotype. The family was reported as nonconsanguineous, and the mode of inheritance sporadic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26523528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 46,XY SEX REVERSAL 3</strong>
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NR5A1, 8-BP DEL, NT1058
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013641</a>
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<p><a href="#9" class="mim-tip-reference" title="Correa, R. V., Domenice, S., Bingham, N. C., Billerbeck, A. E. C., Rainey, W. E., Parker, K. L., Mendonca, B. B. <strong>A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency.</strong> J. Clin. Endocr. Metab. 89: 1767-1772, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070943</a>] [<a href="https://doi.org/10.1210/jc.2003-031240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070943">Correa et al. (2004)</a> reported a novel 8-bp microdeletion of SF1, isolated from a 46,XY patient who presented with gonadal agenesis but normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), that causes premature termination upstream of sequences encoding the activation function-2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wildtype protein in most cell types. The authors stated that this was the first example of an apparent dominant-negative effect of an SF1 mutation in humans. The authors concluded that these findings, which defined an SF1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to patients who present with 46,XY sex reversal but normal adrenal functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 46,XY SEX REVERSAL 3</strong>
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NR5A1, CYS16TER
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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> rs104894123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894123;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/rs104894123?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=rs104894123" 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=rs104894123" 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=RCV000013642" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013642" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013642</a>
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<p>In a 46,XY patient showing gonadal dysgenesis with normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), <a href="#24" class="mim-tip-reference" title="Mallet, D., Bretones, P., Michel-Calemard, L., Dijoud, F., David, M., Morel, Y. <strong>Gonadal dysgenesis without adrenal insufficiency in a 46,XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency.</strong> J. Clin. Endocr. Metab. 89: 4829-4832, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15472171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15472171</a>] [<a href="https://doi.org/10.1210/jc.2004-0670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15472171">Mallet et al. (2004)</a> reported a heterozygous SF1 gene mutation, a C-to-A transversion in exon 2 that replaced cys16 with a stop codon (C16X). The patient showed low basal levels of anti-mullerian hormone (<a href="/entry/600957">600957</a>) and testosterone (T), weak T response to chorionic gonadotropin (see <a href="/entry/118860">118860</a>), and hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation caused premature termination of translation and should abolish all SF1 activity; therefore, haploinsufficiency could explain the deleterious effect of this mutation, suggesting that testis development is more SF1 dose-dependent than adrenal development. The authors concluded that heterozygous mutation can impair adrenal development only if the 2 mechanisms, gene dosage and dominant-negative effects, occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15472171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013643" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013643" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013643</a>
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<p><a href="#15" class="mim-tip-reference" title="Hasegawa, T., Fukami, M., Sato, N., Katsumata, N., Sasaki, G., Fukutani, K., Morohashi, K.-I., Ogata, T. <strong>Testicular dysgenesis without adrenal insufficiency in a 46,XY patient with a heterozygous inactive mutation of steroidogenic factor-1.</strong> J. Clin. Endocr. Metab. 89: 5930-5935, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579739</a>] [<a href="https://doi.org/10.1210/jc.2004-0935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579739">Hasegawa et al. (2004)</a> identified an SF1 mutation in a 27-year-old Japanese patient with a 46,XY karyotype and complete gonadal dysgenesis (SRXY3; <a href="/entry/612965">612965</a>). Sequence analysis of all 7 exons of SF1 revealed a heterozygous 1-bp deletion at exon 2, 18delC, that was predicted to cause a frameshift at codon 6 and result in termination at codon 74 (Asp6fsTer74). Western blot analysis demonstrated no evidence of an amino-truncated SF1 protein despite the 18delC mutation being very close to the natural translation start codon. Transcription analysis indicated that the mutant was transcriptionally inactive and had no dominant-negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, and clitoromegaly. The authors concluded that SF1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH (<a href="/entry/600957">600957</a>) and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579739" 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">rs104894124 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894124;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=rs104894124" 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=rs104894124" 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 British Caucasian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> identified heterozygosity for a de novo val15-to-met (V15M) substitution at a highly conserved residue in the first zinc finger of the DNA-binding domain of SF1. The baby was born with female external genitalia, and bilateral gonads (testes) were palpable in rugose labia. Endocrine studies were consistent with gonadal dysgenesis with impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the baby was raised female. Neither parent carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200175" 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">rs104894125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894125;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=rs104894125" 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=rs104894125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an Italian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> identified heterozygosity for a met78-to-ile (M78I) substitution in a highly conserved region of SF1 between the DNA-binding zinc fingers and the A-box region. The baby was born with normal female external genitalia, and bilateral gonads (testes) were detectable on deep inguinal palpation. Endocrine investigation showed poor testosterone response to human chorionic gonadotropin stimulation, very low mullerian inhibiting substance, and normal adrenal steroids; the patient underwent gonadectomy at 7 months of age. The mother carried the M78I mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200175" 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">rs104894126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894126;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=rs104894126" 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=rs104894126" 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=RCV000013646" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013646" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013646</a>
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<p>In a Fijian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> identified heterozygosity for a gly91-to-ser (G91S) substitution in the A-box region of SF1. At birth, clitoral enlargement and a single perineal opening were noted; gonads (testes) were palpable in the labioscrotal folds. Endocrine studies were consistent with gonadal dysgenesis/impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the child was raised female. The mother carried the G91S mutation. See <a href="#0007">184757.0007</a> and <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200175" 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">rs104894120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894120;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=rs104894120" 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=rs104894120" 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 British Caucasian patient with a 46,XY disorder of sex development (DSD) and normal adrenal function (SRXY3; <a href="/entry/612965">612965</a>), <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> identified heterozygosity for a de novo leu437-to-gln (L437Q) substitution at a highly conserved residue in the ligand-binding domain of SF1, predicted from the crystal structure to form part of the phospholipid-binding pocket. At birth, a small phallus with severe penoscrotal hypospadias and chordee but moderate corporal tissue were noted; bilateral testes were palpable and could be brought down into the scrotum, although bilateral orchipexy was required at age 6 years. Endocrine studies were consistent with impaired androgen biosynthesis. Evaluation of the hypothalamo-pituitary-gonadal axis in late childhood suggested a partial form of hypogonadotropic hypogonadism in addition to a primary testicular defect, and he required supplemental testosterone to induce puberty. <a href="#21" class="mim-tip-reference" title="Lin, L., Philibert, P., Ferraz-de-Souza, B., Kelberman, D., Homfray, T., Albanese, A., Molini, V., Sebire, N. J., Einaudi, S., Conway, G. S., Hughes, I. A., Jameson, J. L., Sultan, C., Dattani, M. T., Achermann, J. C. <strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong> J. Clin. Endocr. Metab. 92: 991-999, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200175[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/10.1210/jc.2006-1672" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200175">Lin et al. (2007)</a> stated that this was the first reported case of a mild phenotype in a patient raised male, and noted that the L437Q mutant retained partial function in several SF1-expressing cell lines. In contrast, the patient's testicular biopsy at 6 years of age showed more marked changes than those seen in 3 46,XY DSD patients with mutations in the NR5A1 gene (<a href="#0007">184757.0007</a>-<a href="#0009">184757.0009</a>) who underwent gonadectomy in infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200175" 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> rs606231206 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231206;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/rs606231206?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=rs606231206" 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=rs606231206" 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=RCV000013648 OR RCV000013649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013648, RCV000013649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013648...</a>
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<p><a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> reported a 17-year-old female with primary amenorrhea who was diagnosed with 46,XY complete gonadal dysgenesis (SRXY3; <a href="/entry/612965">612965</a>). Her mother had a history of irregular menstrual cycles and had become pregnant at the age of 23 years. After giving birth, she had anovulatory cycles that were treated for 2 years with no improvement. At age 35, she was diagnosed as 46,XX primary ovarian insufficiency (POF7; <a href="/entry/612964">612964</a>). Both the mother and child were heterozygous for a frameshift mutation, 666delC, in codon 225 of the NR5A1 gene, truncating the protein from 461 to 295 amino acids. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 350 control subjects of European descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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="0012" class="mim-anchor"></a>
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<strong>.0012 46,XY SEX REVERSAL 3</strong>
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PREMATURE OVARIAN FAILURE 7, INCLUDED
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NR5A1, ASP293ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918655;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=rs121918655" 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=rs121918655" 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=RCV000013650 OR RCV000013651" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013650, RCV000013651" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013650...</a>
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<p><a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> reported an 18-year-old with primary amenorrhea and signs of virilization who was diagnosed with a 46,XY disorder of sex development (SRXY3; <a href="/entry/612965">612965</a>). A sister of the proband presented at the age of 19 years with primary amenorrhea and the diagnosis of 46,XX primary ovarian insufficiency (POF7; <a href="/entry/612964">612964</a>). Mutation analysis in both sibs revealed homozygosity for an 877G-A transition in the NR5A1 gene, resulting in an asp293-to-asn (D293N) substitution. The parents were first cousins. DNA and hormonal studies were performed on 5 of 8 fertile sibs of the proband; 4 of the sibs were heterozygous and a brother did not carry the mutation. Further investigation of the family revealed a female family member with 46,XY complete gonadal dysgenesis but DNA was not available for study; her parents were also first cousins. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 782 control subjects from throughout the world. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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="0013" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0013 46,XY SEX REVERSAL 3</strong>
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PREMATURE OVARIAN FAILURE 7, INCLUDED
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NR5A1, MET1ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918656 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918656;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=rs121918656" 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=rs121918656" 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=RCV000013652 OR RCV000013653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013652, RCV000013653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013652...</a>
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<span class="mim-text-font">
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<p><a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> reported a French child who presented at the age of 12 years with signs of virilization and was diagnosed with 46,XY partial gonadal dysgenesis (SRXY3; <a href="/entry/612965">612965</a>). A sister of the proband presented at the age of 16 years with secondary amenorrhea and was diagnosed with 46,XX primary ovarian insufficiency (POF7; <a href="/entry/612964">612964</a>). The mother was 46 years of age, and menstruation was reportedly normal. The 2 affected sibs and the mother carried a heterozygous 3G-A transition in the first codon of the NR5A1 gene that predicts a met1-to-ile (M1I) substitution. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. An unaffected sib and the father did not have the mutation. The mutation was not found in 350 unaffected French control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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="0014" class="mim-anchor"></a>
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<strong>.0014 46,XY SEX REVERSAL 3</strong>
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PREMATURE OVARIAN FAILURE 7, INCLUDED
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NR5A1, 1-BP DEL, 390G
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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> rs606231207 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231207;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/rs606231207?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=rs606231207" 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=rs606231207" 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=RCV000013654 OR RCV000013655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013654, RCV000013655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013654...</a>
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<p><a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> reported a French child with ambiguous external genitalia and a 46,XY karyotype who was diagnosed with a disorder of sex development (SRXY3; <a href="/entry/612965">612965</a>) and was raised as a boy. After his birth, his mother took oral contraceptives for 2 years until she was 29 years old, after which her menstrual cycles did not reappear. Her diagnosis was 46,XX primary ovarian insufficiency (POF7; <a href="/entry/612964">612964</a>). A heterozygous frameshift mutation, 390delG, was detected in the NR5A1 gene in both the proband and his mother. The mutation is predicted to create a premature termination at codon 295. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not detected in 350 unaffected French control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 PREMATURE OVARIAN FAILURE 7</strong>
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NR5A1, 9-BP DEL, NT691
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs606231208 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231208;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=rs606231208" 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=rs606231208" 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=RCV000013656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013656</a>
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<span class="mim-text-font">
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<p><a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> reported a girl of Roma origin who presented at 12.5 years with short stature and a 46,XX karyotype. She was diagnosed with ovarian failure (POF7; <a href="/entry/612964">612964</a>). Analysis of the NR5A1 gene revealed a heterozygous in-frame 9-bp deletion (691_699delCTGCAGCTG) that results in the loss of 3 amino acids (leu231_leu233) in the N-terminal region of the ligand-binding domain. In silico analysis predicted a change in hydrophobicity of helix 1 of the ligand-binding domain. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The deletion was not observed in 800 control alleles, including samples from 69 unaffected subjects of Roma origin and 56 unaffected subjects from an Indian Gujarati population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" 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> rs200163795 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200163795;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/rs200163795?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=rs200163795" 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=rs200163795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs200749741 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200749741;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/rs200749741?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=rs200749741" 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=rs200749741" 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=RCV000013657 OR RCV000022775 OR RCV001551809 OR RCV001582796 OR RCV002247684 OR RCV003105833 OR RCV003105834 OR RCV003454713 OR RCV003967675 OR RCV003977699" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013657, RCV000022775, RCV001551809, RCV001582796, RCV002247684, RCV003105833, RCV003105834, RCV003454713, RCV003967675, RCV003977699" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013657...</a>
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<p>In a 4-month-old girl of Senegalese origin who presented with hypertrophy of the clitoris, <a href="#22" class="mim-tip-reference" title="Lourenco, D., Brauner, R., Lin, L., De Perdigo, A., Weryha, G., Muresan, M., Boudjenah, R., Guerra-Junior, G., Maciel-Guerra, A. T., Achermann, J. C., McElreavey, K., Bashamboo, A. <strong>Mutations in the NR5A1 associated with ovarian insufficiency.</strong> New Eng. J. Med. 360: 1200-1210, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19246354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19246354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19246354[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/10.1056/NEJMoa0806228" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19246354">Lourenco et al. (2009)</a> found elevated FSH, indicating ovarian insufficiency (POF7; <a href="/entry/612964">612964</a>). Molecular analysis identified 2 mutations in the NR5A1 gene that occurred in cis: a 368G-C transversion resulting in a gly123-to-ala (G123A) substitution, and a 386C-T transition resulting in a pro129-to-leu (P129L) substitution. Both mutations occurred in the hinge domain of the protein. The parents were not available for study. Functional studies indicated that the mutations substantially impaired NR5A1 transactivational activity. Neither mutation was found in 479 unaffected control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19246354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Congolese men with azoospermia and 1 Tunisian man with severe oligospermia (SPGF8; <a href="/entry/613957">613957</a>), <a href="#5" class="mim-tip-reference" title="Bashamboo, A., Ferraz-de-Souza, B., Lourenco, D., Lin, L., Sebire, N. J., Montjean, D., Bignon-Topalovic, J., Mandelbaum, J., Siffroi, J.-P., Christin-Maitre, S., Radhakrishna, U., Rouba, H., Ravel, C., Seeler, J., Achermann, J. C., McElreavey, K. <strong>Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.</strong> Am. J. Hum. Genet. 87: 505-512, 2010. Note: Erratum. Am. J. Hum. Genet. 87: 736 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20887963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20887963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20887963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20887963">Bashamboo et al. (2010)</a> identified heterozygosity for the cis-occurring G123A/P129L mutations in the NR5A1 gene. The authors noted that all of the individuals reported to carry this double mutation were of African origin, suggesting that this is likely a founder mutation. One of the men carrying this mutation was observed to have progressive loss of germ cell quantity and quality over a 2-year period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20887963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 SPERMATOGENIC FAILURE 8</strong>
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NR5A1, PRO131LEU
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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> rs387906690 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906690;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/rs387906690?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=rs387906690" 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=rs387906690" 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=RCV000022776" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022776" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022776</a>
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<p>In a 41-year-old Sri Lankan man with azoospermia (SPGF8; <a href="/entry/613957">613957</a>), <a href="#5" class="mim-tip-reference" title="Bashamboo, A., Ferraz-de-Souza, B., Lourenco, D., Lin, L., Sebire, N. J., Montjean, D., Bignon-Topalovic, J., Mandelbaum, J., Siffroi, J.-P., Christin-Maitre, S., Radhakrishna, U., Rouba, H., Ravel, C., Seeler, J., Achermann, J. C., McElreavey, K. <strong>Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.</strong> Am. J. Hum. Genet. 87: 505-512, 2010. Note: Erratum. Am. J. Hum. Genet. 87: 736 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20887963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20887963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20887963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20887963">Bashamboo et al. (2010)</a> identified heterozygosity for a 392C-T transition in the NR5A1 gene, resulting in a pro131-to-leu substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated a greater than 60% reduction in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (<a href="/entry/118485">118485</a>) and AMH (<a href="/entry/600957">600957</a>), compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20887963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 SPERMATOGENIC FAILURE 8</strong>
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NR5A1, GLY212SER
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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> rs201095702 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201095702;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/rs201095702?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=rs201095702" 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=rs201095702" 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=RCV000022777" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022777" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022777</a>
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<p>In a 37-year-old French-Vietnamese man with severe oligozoospermia (SPGF8; <a href="/entry/613957">613957</a>), <a href="#5" class="mim-tip-reference" title="Bashamboo, A., Ferraz-de-Souza, B., Lourenco, D., Lin, L., Sebire, N. J., Montjean, D., Bignon-Topalovic, J., Mandelbaum, J., Siffroi, J.-P., Christin-Maitre, S., Radhakrishna, U., Rouba, H., Ravel, C., Seeler, J., Achermann, J. C., McElreavey, K. <strong>Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.</strong> Am. J. Hum. Genet. 87: 505-512, 2010. Note: Erratum. Am. J. Hum. Genet. 87: 736 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20887963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20887963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20887963[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20887963">Bashamboo et al. (2010)</a> identified heterozygosity for a 634G-A transition in the NR5A1 gene, resulting in a gly212-to-ser (G212S) substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated approximately 80% and 70% reductions in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (<a href="/entry/118485">118485</a>) and AMH (<a href="/entry/600957">600957</a>), respectively, compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20887963" 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">rs886039769 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039769;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=rs886039769" 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=rs886039769" 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=RCV000256210 OR RCV000490553 OR RCV001820799 OR RCV001855015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000256210, RCV000490553, RCV001820799, RCV001855015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000256210...</a>
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<p>In 5 patients from 4 unrelated families with 46,XX sex reversal (SRXX4; <a href="/entry/617480">617480</a>), <a href="#4" class="mim-tip-reference" title="Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., Buonocore, F., Barseghyan, H., Bingham, N., Rosenfeld, J. A., Mulukutla, S. N., Jain, M., and 25 others. <strong>A recurrent p.arg92trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.</strong> Hum. Molec. Genet. 25: 3446-3453, 2016. Note: Erratum: Hum. Molec. Genet. 25: 5286 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27378692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27378692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27378692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27378692">Bashamboo et al. (2016)</a> identified a c.274C-T transition in the NR5A1 gene that resulted in an arg-to-trp substitution at codon 92 (R92W). In 1 of these families, a sister had 46,XY sex reversal (SRXY3; <a href="/entry/612965">612965</a>) due to the same variant. In 2 families, the variant was maternally inherited, in 1 it occurred as a de novo event, and in 1 family the mutation was not present in the father, but the mother was deceased and no DNA was available. The variant was absent from the dbSNP (build 138), ExAC, and 1000 Genomes Project databases, and from an internal database containing exomes of 400 individuals as well as more than 1,000 fertile controls Sanger sequenced for NR5A1. The arg92 residue in NR5A1 is evolutionarily conserved to zebrafish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27378692" 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 3 unrelated probands with 46,XX (ovo)testicular disorder of sexual development (DSD), <a href="#3" class="mim-tip-reference" title="Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M. <strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong> Genet. Med. 19: 367-376, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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/gim.2016.118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27490115">Baetens et al. (2017)</a> found a c.274C-T transition in exon 4 of the NR5A1 gene (c.274C-T, NM_004959.4) that resulted in an R92W substitution in the protein. Several unaffected female first-degree relatives of the probands from each of the families also carried this mutation, suggesting that this variant is weakly penetrant. A potential founder effect was suggested by haplotype analysis. The arg92 residue is highly evolutionarily conserved to zebrafish and located in the Ftz-F1 region, probably involved with DNA-binding specificity and stability. The R92W mutation was absent from the Exome Sequencing Project (ESP), ExAC, Genome of the Netherlands (GoNL), and 1000 Genomes Project databases and from an in-house exome database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27490115" 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="#16" class="mim-tip-reference" title="Igarashi, M., Takasawa, K., Hakoda, A., Kanno, J., Takada, S., Miyado, M., Baba, T., Morohashi, K., Tajima, T., Hata, K., Nakabayashi, K., Matsubara, Y., Sekido, R., Ogata, T., Kashimada, K., Fukami, M. <strong>Identical NR5A1 missense mutations in 2 unrelated 46,XX individuals with testicular tissues.</strong> Hum. Mutat. 38: 39-42, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27610946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27610946</a>] [<a href="https://doi.org/10.1002/humu.23116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27610946">Igarashi et al. (2017)</a> identified the R92W mutation (c.274C-T, NM_004959.4) in 2 unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The mutation was absent from the clinically normal mothers and from 200 Japanese controls. One of the fathers, who was unaffected, carried the mutation; the other father was not available for analysis. In vitro assays showed that the mutant protein was less sensitive than wildtype to NR0B1 (<a href="/entry/300473">300473</a>)-induced suppression on the SOX9 (<a href="/entry/608160">608160</a>) enhancer element. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27610946" 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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Achermann, J. C., Ozisik, G., Ito, M., Orun, U. A., Harmanci, K., Gurakan, B., Jameson, J. L.
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<strong>Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932325</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932325" 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/10.1210/jcem.87.4.8376" target="_blank">Full Text</a>]
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Baetens, D., Stoop, H., Peelman, F., Todeschini, A.-L., Rosseel, T., Coppieters, F., Veitia, R. A., Looijenga, L. H. J., De Baere, E., Cools, M.
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<strong>NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development.</strong>
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Genet. Med. 19: 367-376, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27490115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27490115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27490115[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=27490115" 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/gim.2016.118" target="_blank">Full Text</a>]
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Bashamboo, A., Donohoue, P. A., Vilain, E., Rojo, S., Calvel, P., Seneviratne, S. N., Buonocore, F., Barseghyan, H., Bingham, N., Rosenfeld, J. A., Mulukutla, S. N., Jain, M., and 25 others.
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<strong>A recurrent p.arg92trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.</strong>
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Hum. Molec. Genet. 25: 3446-3453, 2016. Note: Erratum: Hum. Molec. Genet. 25: 5286 only, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27378692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27378692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27378692[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=27378692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddw186" target="_blank">Full Text</a>]
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Bashamboo, A., Ferraz-de-Souza, B., Lourenco, D., Lin, L., Sebire, N. J., Montjean, D., Bignon-Topalovic, J., Mandelbaum, J., Siffroi, J.-P., Christin-Maitre, S., Radhakrishna, U., Rouba, H., Ravel, C., Seeler, J., Achermann, J. C., McElreavey, K.
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<strong>Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.</strong>
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Am. J. Hum. Genet. 87: 505-512, 2010. Note: Erratum. Am. J. Hum. Genet. 87: 736 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20887963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20887963</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20887963[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=20887963" 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.ajhg.2010.09.009" target="_blank">Full Text</a>]
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Biason-Lauber, A., Schoenle, E. J.
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<strong>Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency.</strong>
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Am. J. Hum. Genet. 67: 1563-1568, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11038323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11038323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11038323[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=11038323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/316893" target="_blank">Full Text</a>]
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Bland, M. L., Jamieson, C. A. M., Akana, S. F., Bornstein, S. R., Eisenhofer, G., Dallman, M. F., Ingraham, H. A.
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<strong>Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11121051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11121051</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11121051[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=11121051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.97.26.14488" target="_blank">Full Text</a>]
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Calvo, R. M., Asuncion, M., Telleria, D., Sancho, J., San Millan, J. L., Escobar-Morreale, H. F.
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<strong>Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women.</strong>
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J. Clin. Endocr. Metab. 86: 1746-1749, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297612</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297612" 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/10.1210/jcem.86.4.7424" target="_blank">Full Text</a>]
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Correa, R. V., Domenice, S., Bingham, N. C., Billerbeck, A. E. C., Rainey, W. E., Parker, K. L., Mendonca, B. B.
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<strong>A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency.</strong>
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J. Clin. Endocr. Metab. 89: 1767-1772, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070943" 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/10.1210/jc.2003-031240" target="_blank">Full Text</a>]
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Figueiredo, B. C., Cavalli, L. R., Pianovski, M. A. D., Lalli, E., Sandrini, R., Ribeiro, R. C., Zambetti, G., DeLacerda, L., Rodrigues, G. A., Haddad, B. R.
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<strong>Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors.</strong>
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J. Clin. Endocr. Metab. 90: 615-619, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15546904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15546904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15546904" 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/10.1210/jc.2004-0942" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M205786200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)80480-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/mend.12.5.0100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.23116" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20588" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590178" 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/s0092-8674(00)81172-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.jbchem.a124918" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1996.1343" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature06944" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(94)90050-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000452888" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1995.1204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(95)80059-u" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10230404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10230404</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10230404" 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/s1097-2765(00)80479-7" target="_blank">Full Text</a>]
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Tremblay, J. J., Viger, R. S.
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<strong>A mutated form of steroidogenic factor 1 (SF-1 G35E) that causes sex reversal in humans fails to synergize with transcription factor GATA-4.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M305485200" target="_blank">Full Text</a>]
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<strong>The Wilms tumor suppressor WT1 regulates early gonadal development by activation of Sf1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12130543[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=12130543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1101/gad.220102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1677/jme.0.0170139" target="_blank">Full Text</a>]
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Xue, Q., Lin, Z., Yin, P., Milad, M. P., Cheng, Y.-H., Confino, E., Reierstad, S., Bulun, S. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17519303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17519303</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17519303" 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/10.1210/jc.2007-0494" target="_blank">Full Text</a>]
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Bao Lige - updated : 05/11/2022
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Ada Hamosh - updated : 05/24/2017<br>Marla J. F. O'Neill - updated : 08/09/2016<br>Matthew B. Gross - updated : 5/2/2016<br>Patricia A. Hartz - updated : 6/3/2014<br>Marla J. F. O'Neill - updated : 5/11/2011<br>Ada Hamosh - updated : 7/28/2009<br>Ada Hamosh - updated : 7/11/2008<br>Marla J. F. O'Neill - updated : 3/24/2008<br>John A. Phillips, III - updated : 3/24/2008<br>John A. Phillips, III - updated : 1/28/2008<br>Marla J. F. O'Neill - updated : 1/28/2008<br>John A. Phillips, III - updated : 1/18/2008<br>John A. Phillips, III - updated : 12/18/2006<br>John A. Phillips, III - updated : 8/21/2006<br>Patricia A. Hartz - updated : 8/15/2006<br>John A. Phillips, III - updated : 4/4/2006<br>John A. Phillips, III - updated : 7/25/2005<br>John A. Phillips, III - updated : 10/30/2002<br>Cassandra L. Kniffin - updated : 9/10/2002<br>John A. Phillips, III - updated : 7/13/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Victor A. McKusick - updated : 12/18/2000<br>John A. Phillips, III - updated : 11/10/2000<br>Stylianos E. Antonarakis - updated : 7/2/1999<br>Victor A. McKusick - updated : 5/25/1999<br>John A. Phillips, III - updated : 4/15/1999<br>Stylianos E. Antonarakis - updated : 6/1/1998<br>Jennifer P. Macke - updated : 4/3/1997<br>Alan F. Scott - updated : 9/27/1995
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Victor A. McKusick : 6/21/1994
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carol : 09/12/2022<br>carol : 05/12/2022<br>mgross : 05/11/2022<br>carol : 04/23/2021<br>alopez : 02/16/2018<br>carol : 11/14/2017<br>carol : 08/25/2017<br>alopez : 05/24/2017<br>alopez : 05/24/2017<br>alopez : 05/24/2017<br>alopez : 05/24/2017<br>alopez : 08/09/2016<br>carol : 06/23/2016<br>mgross : 5/2/2016<br>alopez : 10/30/2014<br>mgross : 6/9/2014<br>mcolton : 6/3/2014<br>carol : 10/22/2012<br>carol : 3/13/2012<br>carol : 5/11/2011<br>alopez : 3/24/2011<br>alopez : 3/15/2011<br>terry : 9/9/2010<br>mgross : 1/25/2010<br>joanna : 1/25/2010<br>terry : 8/20/2009<br>terry : 8/18/2009<br>terry : 8/17/2009<br>carol : 8/14/2009<br>carol : 8/14/2009<br>terry : 7/28/2009<br>alopez : 2/9/2009<br>ckniffin : 1/21/2009<br>terry : 9/25/2008<br>alopez : 7/15/2008<br>terry : 7/11/2008<br>wwang : 3/28/2008<br>wwang : 3/26/2008<br>terry : 3/24/2008<br>carol : 3/24/2008<br>carol : 1/28/2008<br>terry : 1/18/2008<br>alopez : 12/18/2006<br>ckniffin : 12/14/2006<br>alopez : 8/21/2006<br>mgross : 8/15/2006<br>alopez : 4/4/2006<br>wwang : 12/13/2005<br>alopez : 7/25/2005<br>terry : 3/16/2005<br>joanna : 3/17/2004<br>carol : 2/23/2004<br>carol : 12/9/2003<br>alopez : 10/30/2002<br>alopez : 10/30/2002<br>carol : 9/10/2002<br>ckniffin : 8/30/2002<br>ckniffin : 8/26/2002<br>cwells : 7/19/2001<br>cwells : 7/13/2001<br>cwells : 1/25/2001<br>terry : 1/12/2001<br>mgross : 12/18/2000<br>mgross : 12/18/2000<br>terry : 12/12/2000<br>terry : 11/10/2000<br>mgross : 9/24/1999<br>mgross : 7/9/1999<br>kayiaros : 7/2/1999<br>kayiaros : 7/2/1999<br>alopez : 5/27/1999<br>terry : 5/25/1999<br>mgross : 4/16/1999<br>mgross : 4/15/1999<br>carol : 6/2/1998<br>terry : 6/1/1998<br>alopez : 5/1/1997<br>alopez : 4/7/1997<br>alopez : 4/4/1997<br>alopez : 4/4/1997<br>alopez : 4/3/1997<br>mark : 1/29/1997<br>mark : 12/12/1995<br>terry : 3/7/1995<br>carol : 1/20/1995<br>jason : 6/21/1994
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<h3>
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<span class="mim-font">
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<strong>*</strong> 184757
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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FUSHI TARAZU FACTOR, DROSOPHILA, HOMOLOG 1; FTZF1; FTZ1<br />
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STEROIDOGENIC FACTOR 1; SF1<br />
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ADRENAL 4 BINDING PROTEIN; AD4BP<br />
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EMBRYONAL LTR-BINDING PROTEIN; ELP
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NR5A1</em></strong>
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</span>
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</p>
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<p>
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<strong>
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<em>
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Cytogenetic location: 9q33.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:124,481,236-124,507,399 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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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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<tbody>
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<td rowspan="5">
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<span class="mim-font">
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9q33.3
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<td>
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<span class="mim-font">
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46XX sex reversal 4
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<span class="mim-font">
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617480
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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46XY sex reversal 3
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<span class="mim-font">
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612965
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Adrenocortical insufficiency
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<span class="mim-font">
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612964
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Premature ovarian failure 7
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<span class="mim-font">
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612964
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Spermatogenic failure 8
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<span class="mim-font">
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613957
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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</table>
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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>NR5A1 is a transcription factor belonging to the nuclear receptor superfamily. It binds the core motif AGGTCA and regulates many genes involved in reproduction, steroidogenesis, and sexual differentiation (summary by Tremblay and Viger, 2003). </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>Ninomiya et al. (1995) cloned 4 splice variants of mouse Nr5a1, which they called Elp. The 4 variants, Elp1, Elp2, Elp3, and Ad4bp/Sf1, encode 3 isoforms, as Elp3 and Ad4bp/Sf1 have identical coding sequences but differ in their 5-prime noncoding regions. All isoforms contain a DNA-binding domain, a proline-rich region, and region II. Elp2 and Elp3/Ad4bp/Sfl also have region III, which is missing in Elp1. RT-PCR analysis showed complex expression of the variants in mouse tissues, with only embryonal carcinoma cells expression all 4 variants. </p><p>Oba et al. (1996) cloned the genomic DNA of the human SF1 gene, the mammalian homolog of Drosophila Ftzf1. They noted that the deduced amino acid sequence of human SF1 consists of 461 amino acids. </p><p>By screening an embryonic adrenal gland cDNA library, Wong et al. (1996) cloned human NR5A1, which they called SF1. The deduced 461-amino acid protein contains 2 N-terminal zinc finger DNA-binding domains, followed by an FTZF1 box, a hinge region, a ligand-binding domain, and a C-terminal AF2 transactivation domain. SF2 also has an evolutionarily conserved consensus phosphorylation motif. Human SF2 shares 93 to 95% amino acid identity with cow, rat, and mouse Sf2. The authors noted that mouse Sf2 is alternatively spliced to produce 4 distinct transcripts. </p><p>Using immunohistochemistry in rats to analyze NR5A1 expression during steroidogenesis and spermatogenesis, Kojima et al. (2006) observed expression in both Leydig and Sertoli cells in the 7-day-old rat, but expression levels decreased in Sertoli cells by 21 days, and was present only in Leydig cells in the 56-day-old sexually mature rat. In humans, quantitative RT-PCR and Western blot analysis of testicular tissue obtained from males at ages ranging from 1 year to 26 years showed increased expression with increasing age during testicular development. Expression patterns were similar to those seen in rats, with NR5A1 expressed in both Sertoli and Leydig cells in a 1-year-old boy, but showing decreased expression in Sertoli cells in an 8-year-old boy. In pubertal and adult testes NR5A1 was abundantly expressed in the nuclei of Leydig cells, with only a few Sertoli cells showing faint expression. Kojima et al. (2006) concluded that expression of NR5A1 is developmentally regulated, with maximal expression during puberty and high expression after puberty. </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>Oba et al. (1996) determined that the human SF1 gene spans 30 kb of genomic DNA and is split into 7 exons, including the noncoding first exon. </p><p>Wong et al. (1996) determined that the NR5A1 gene contains 7 exons and spans 22 kb. </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>Taketo et al. (1995) mapped the human NR5A1 gene to chromosome 9q33 by fluorescence in situ hybridization. </p><p>By linkage analysis using interspecific backcross mice, Swift and Ashworth (1995) mapped the Nr5a1 gene to mouse chromosome 2. Taketo et al. (1995) further mapped the mouse gene to the proximal quarter of the chromosome. </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>Luo et al. (1994) reviewed studies implicating SF1 in gonadal differentiation and steroidogenesis. Studies in adrenocortical cells implicated an orphan nuclear receptor, alternatively designated steroidogenic factor-1 (SF1) or adrenal 4-binding protein (AD4BP), in the gene regulation of the 3 enzymes that are required for the biosynthesis of corticosteroids: cholesterol side chain cleavage enzyme (CYP11A1; 118485), steroid 21-hydroxylase (CYP21A2; 613815), and the aldosterone synthase isozyme of steroid 11-beta-hydroxylase (CYP11B2; 124080). Consistent with this postulated role, SF1 in adult mice is expressed in all primary steroidogenic tissues, including the adrenal cortex, testicular Leydig cells, and ovarian theca and granulosa cells and corpus luteum. Furthermore, it is expressed in the urogenital ridge of mouse embryos at embryonic day 9-9.5, the earliest stage of organogenesis of the developing gonads, and is also expressed in fetal Sertoli cells. Structural analysis of an SF1 cDNA showed that it closely matches a mouse cDNA isolated from an embryonal carcinoma cell cDNA library and designated embryonal long terminal repeat-binding protein (ELP) because it binds regulatory elements in retroviral long terminal repeats. Isolation and characterization of genomic clones demonstrated that both SF1 and ELP arose from the same structural gene by alternative promoter usage and splicing. Especially in their shared zinc finger DNA-binding domains, SF1 and ELP closely resembled an orphan nuclear receptor isolated from Drosophila, designated fushi tarazu factor-1, or FTZ-F1 (Lala et al., 1992). For that reason, the mouse gene was designated Ftz-F1. The homologous gene in Drosophila also encodes 2 distinct transcripts proposed to play important roles in Drosophila development. </p><p>Shen et al. (1994) proposed that SF1 regulates MIS (600957) in vivo and participates directly in the process of mammalian sex determination. This conclusion was based on several observations. First, in primary Sertoli cells, SF1 regulates the MIS gene by binding to a conserved upstream regulatory element. Second, in heterologous (HeLa) cells, MIS gene activation by SF1 requires removal of the SF1 ligand-binding domain, implicating a Sertoli cell-specific ligand or cofactor. Finally, the sexually dimorphic expression of SF1 during development coincides with MIS expression and mullerian duct regression. </p><p>Using transfected NIH3T3 cells, Ninomiya et al. (1995) showed that mouse Elp1 functioned as a transcription repressor, whereas the other Elp isoforms functioned as transactivators. </p><p>Nachtigal et al. (1998) showed that WT1(-KTS) (607102) isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (194080), fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; 300018) gene, DAX1 (NR0B1; 300473), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. Nachtigal et al. (1998) proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation. </p><p>To determine the molecular mechanisms underlying transcriptional regulation of SF1 gene expression in the pituitary, Harris and Mellon (1998) studied a series of deletion and point mutations in the SF1 promoter region for transcriptional activity in alpha-T3-1 and L-beta-T2 (pituitary gonadotrope), CV-1, JEG-3, and Y1 (adrenocortical) cell lines. Their results indicated that maximal expression of the SF1 promoter in all cell types requires an E box element at -82/-77. This E box sequence (CACGTG) is identical to the binding element for upstream stimulatory factor-1 (USF1; 191523), a member of the helix-loop-helix family of transcription factors. Studies of the SF1 gene E box element using gel mobility shift and antibody supershift assays indicated that USF1 may be a key transcriptional regulator of SF1 gene expression. </p><p>Hammer et al. (1999) demonstrated that maximal SF1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (ser-203) located in a major activation domain (AF1) of the protein. Moreover, phosphorylation-dependent SF1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway (see 603014). They proposed that this single modification of SF1 and the subsequent recruitment of nuclear receptor cofactors couple extracellular signals to steroid and peptide hormone synthesis, thereby maintaining dynamic homeostatic responses in stress and reproduction. Tremblay et al. (1999) demonstrated that phosphorylation of AF1 by MAPK leads to the recruitment of steroid receptor coactivator-1 (602691) by estrogen receptor-beta (601663) in vitro. </p><p>Morohashi (1999) reviewed the gonadal and extragonadal functions of AD4BP/SF1, focusing on the developmental aspects. Gene disruption studies had shown that AD4BP/SF1, originally identified as a steroidogenic tissue-specific transcription factor, plays crucial roles in the process of nonsteroidogenic as well as steroidogenic tissue differentiation. Although the mechanisms underlying differentiation of these tissues were still under investigation, spatial and temporal expression profiles of the AD4BP/SF1 gene supported its contribution to tissue development from the earliest stages of ontogeny. </p><p>Gizard et al. (2002) found that coexpression of SF1 and TREP132 (TRERF1; 610322) in an adrenal carcinoma cell line increased CYP11A1 promoter activity, and pull-down, 2-hybrid, and coimmunoprecipitation analyses confirmed SF1-TREP132 interaction. Deletion and mutation analysis showed that the proximal activation domain and AF2 hexamer motif of SF1 interacted with the LxxLL motif in the N-terminal region of TREP132. Coexpression of CBP (CREBBP; 600140)/p300 (EP300; 602700) with SF1 and TREP132 resulted in a synergistic effect on CYP11A1 promoter activity. </p><p>Xue et al. (2007) identified a CpG island flanking the SF1 promoter and exon I region (-85/+239) and determined its methylation patterns in endometrial and endometriotic cells. SF1 mRNA and protein levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells (p less than 0.001). Bisulfite sequencing showed strikingly increased methylation in endometrial cells, compared with endometriotic cells (p less than 0.001). Xue et al. (2007) concluded that this was the first demonstration of methylation-dependent regulation of SF1 in any mammalian tissue and suggested that these findings pointed to a new mechanism for targeting local estrogen biosynthesis in endometriosis (131200). </p><p>Sekido and Lovell-Badge (2008) demonstrated that SRY (480000) binds to multiple elements within a Sox9 (608160) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with SF1. Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Sekido and Lovell-Badge (2008) concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal. </p><p>Kojima et al. (2006) analyzed expression levels of NR5A1 mRNA in testicular tissue from 22 patients with nonobstructive azoospermia, and detected NR5A1 in all specimens. Quantitative RT-PCR showed a significant positive correlation between the expression level of NR5A1 and serum testosterone concentration; however, there was no correlation with the severity of histologic pathology observed in the testicular tissue. </p><p>Bashamboo et al. (2016) found that in contrast to mouse, where nr5a1 is expressed specifically in the somatic cells of the testis and only trace expression is seen in the early ovary, in human embryos expression of NR5A1 is similar in ovary and testis and higher than in other tissues. </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>46,XY Sex Reversal 3</em></strong></p><p>
|
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Steroidogenic factor-1 is an orphan nuclear receptor that regulates the transcription of an array of genes involved in reproduction, steroidogenesis, and male sexual differentiation, including AMH (600957), DAX1, CYP11A1, steroidogenic acute regulatory protein (STAR; 600617), and those encoding steroid hydroxylases, gonadotropins, and aromatase. Disruption of the Ftzf1 gene in mice causes failure of adrenal and gonadal development, XY sex reversal, persistence of mullerian structures in males, and abnormalities of the hypothalamus and pituitary gonadotropes (see later). In a phenotypically female patient who presented with primary adrenal failure in the first 2 weeks of life and had a 46,XY karyotype (SRXY3; 612965), Achermann et al. (1999) identified heterozygosity for a 2-bp mutation in exon 3 (184757.0001) of the SF1 gene, which encodes part of the DNA-binding domain. By site-directed mutagenesis, Achermann et al. (1999) created the G35E mutant form of SF1 for use in functional studies. The mutation did not interfere with protein translation, stability, or nuclear localization, but it eliminated the binding of SF1 to a canonical binding site. Consistent with its impaired DNA binding, the G35E SF1 mutant did not transactivate a known SF1-responsive reporter gene. The mutant SF1 did not exhibit dominant-negative activity when coexpressed with wildtype SF1. The SF1 mutation in this patient caused complete XY sex reversal, including normal female external genitalia and retention of the uterus. This contrasts with disorders of steroid biosynthesis, in which no uterus is present. The findings provided evidence that SF1 regulates the regression of mullerian structures in humans, either through direct actions on AMH or secondary to an abnormality of Sertoli cell development or function. </p><p>Lin et al. (2006) studied the prevalence of DAX1 and SF1 mutations in 117 children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). SF1 mutations causing adrenal failure were found in only 2 patients with 46,XY gonadal dysgenesis. Lin et al. (2006) concluded that SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals. </p><p>Lin et al. (2007) analyzed the NR5A1 gene in 30 patients with 46,XY disorders of sex development and identified heterozygous missense mutations in 4 patients (184757.0007-184757.0010, respectively). Three of the mutations showed loss of function in adrenal, Leydig, and Sertoli cells lines, but an L437Q ligand-binding domain mutant identified in 1 of the patients (184757.0010) retained partial activity in these cell systems, consistent with the milder clinical phenotype of that patient (hypospadias, male gender assignment). </p><p>Kohler et al. (2008) analyzed the NR5A1 gene in 27 German 46,XY patients with severe underandrogenization without adrenal insufficiency and identified heterozygous mutations in 5 (18.5%) patients; the authors concluded that NR5A1 mutations are a relatively frequent cause of 46,XY disorders of sex development. </p><p><strong><em>NR5A1-Related Adrenal Insufficiency</em></strong></p><p>
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|
Biason-Lauber and Schoenle (2000) described a female patient with adrenal insufficiency and no apparent defect in ovarian maturation (see 612964), despite a heterozygous mutation in the NR5A1 gene (184757.0002). The authors concluded that NR5A1 has a crucial role in adrenal gland formation in both sexes. </p><p>Guran et al. (2016) described a 2-week-old girl with primary adrenal insufficiency, 46,XX karyotype, normal female phenotype, and no evidence of ovarian insufficiency. She carried a homozygous arg92-to-gln mutation in NR5A1 (R92Q; 184757.0003). </p><p><strong><em>Adrenocortical Tumors</em></strong></p><p>
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|
Using comparative genomic hybridization, Figueiredo et al. (2005) detected a consistent gain of chromosome 9q or a portion of it in 8 of 9 cases of pediatric adrenocortical tumors (ACTs) and amplification of 9q34 in the majority of these cases. They also examined if the SF1 gene, which is located in this chromosomal region and plays an important role in the development and function of the adrenal cortex, is amplified in these ACT cases. They detected increased copy number of the SF1 gene in all 8 cases with 9q gain, suggesting an association between an increased copy number of the SF1 gene and adrenocortical tumorigenesis. </p><p><strong><em>Premature Ovarian Failure 7</em></strong></p><p>
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|
Lourenco et al. (2009) sequenced the NR5A1 gene in 4 families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. They identified mutations in patients with premature ovarian failure (POF7; 612964) as well as in patients with 46,XY disorders (184757.0011-184757.0016). None of the affected subjects had clinical signs of adrenal insufficiency. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. None of the mutations were observed in more than 700 control alleles. </p><p><strong><em>Spermatogenic Failure 8</em></strong></p><p>
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|
Bashamboo et al. (2010) analyzed the candidate gene NR5A1 in 315 men with idiopathic spermatogenic failure and identified heterozygous missense mutations in 7 of them (see, e.g., 184757.0016-184757.0018). This form of the disorder is designated spermatogenic failure-8 (SPGF8; 613957). None of the mutations were found in more than 2,100 control samples, and analysis of the entire coding region of NR5A1 in 370 fertile men (father of at least 2 children) or 359 normospermic men revealed no rare allelic variants. </p><p><strong><em>46,XX Sex Reversal 4</em></strong></p><p>
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|
Using whole-exome, whole-genome, or direct sequencing, Bashamboo et al. (2016) showed that a specific recurrent heterozygous missense mutation, arg92-to-trp (R92W; 184757.0019), in the accessory DNA-binding region of NR5A1 was associated with a variable degree of testis development in 46,XX children and adults from 4 unrelated families (SRXX4; 617480). Remarkably, in 1 family a sib of the proband, raised as a girl and carrying this NR5A1 mutation, was found to have a 46,XY karyotype and partial testicular dysgenesis (SRXY3; 612965). Bashamboo et al. (2016) concluded that these findings highlighted how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals, and represented the first missense mutation causing isolated, nonsyndromic 46,XX testicular/ovotesticular DSD in humans. </p><p>Baetens et al. (2017) screened a cohort of 11 unrelated cases and 2 sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD) using whole-exome sequencing in 9 patients, targeted resequencing in 4, and haplotyping. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. Baetens et al. (2017) identified a novel heterozygous NR5A1 mutation, c.274C-T (arg92 to trp, R92W; 184757.0019), in 3 unrelated patients. The arg92 residue is highly conserved and located in the Ftz-F1 region, which is thought to be involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1 (300120), a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 (605597) and testicular SRY (480000)-independent SOX9 (608160) expression was observed. Baetens et al. (2017) proposed NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD and hypothesized that the R92W mutation results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. Baetens et al. (2017) concluded that their study supported a role for NR5A1 in testis differentiation in the XX gonad. In the first family reported by Baetens et al. (2017), the proband's healthy sister, father, paternal uncle and grandfather all carried the R92W mutation in NR5A1. A younger sister of the second proband carried the same mutation and displayed normal puberty. In the third family, the proband's 2 younger brothers and mother, all unaffected, carried the R92W mutation. All affected mutation carriers shared a common haplotype spanning a 1.5-Mb region. No other known variants associated with 46,XX sex reversal were identified in any of the probands. </p><p>In a 46,XX patient with bilateral ovotestes, Swartz et al. (2017) identified a heterozygous arg92-to-gln (R92Q; 184757.0003) mutation, inherited from the unaffected father. This mutation had previously been reported in a patient with 46,XY DSD (SRXY3; 612965) and in a 46,XX infant with normal female phenotype and adrenal insufficiency (see 612964). </p><p><strong><em>Exclusion Studies</em></strong></p><p>
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Calvo et al. (2001) used heteroduplex analysis to screen the genes encoding STAR, SF1, DAX1, and CYP11A1 for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. Two variants in the SF1 gene were identified. The authors concluded that mutations in STAR, SF1, CYP11A1, and DAX1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities found in these women. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To examine the role of Ftzf1 in intact mice, Luo et al. (1994) used targeted disruption of the Ftzf1 gene. Despite normal survival in utero, all Ftzf1-null animals died by postnatal day 8; these animals lacked adrenal glands and gonads and were severely deficient in corticosterone, supporting adrenocortical insufficiency as the probable cause of death. Male and female Ftzf1-null mice had female internal genitalia, despite complete gonadal agenesis. These studies established that the Ftzf1 gene is essential for sexual differentiation and formation of the primary steroidogenic tissues. Normal male sex differentiation requires that Sertoli cells in the embryonic testes produce mullerian-inhibiting substance (AMH; 600957), a TGF-beta-like hormone that causes mullerian duct regression. </p><p>Because of the demonstration that reduced expression of steroidogenic factor-1 in patients leads to adrenal failure, Bland et al. (2000) examined SF1 heterozygous mice as a potential model for delineating the mechanisms underlying this disorder. They showed that SF1 +/- mice exhibit adrenal insufficiency resulting from profound defects in adrenal development and organization. However, compensatory mechanisms, such as cellular hypertrophy and increased expression of the rate-limiting steroidogenic protein (600617), help to maintain adrenal function at near normal capacity under basal conditions. In contrast, adrenal deficits in SF1 heterozygotes were revealed under stressful conditions, demonstrating that normal gene dosage of SF1 is required for mounting an adequate stress response. The findings predicted that natural variations leading to reduced SF1 function may underlie some forms of subclinical adrenal insufficiency that become life-threatening during traumatic stress. </p><p>Using transgenic mice, Wilhelm and Englert (2002) showed that Wt1(-KTS) binds to 4 promoter sequences of the Sf1 gene, and that Wt1(-KTS) and Lhx9 (606066) have an additive effect in activating the Sf1 promoter. Wt1 was also shown to regulate Dax1 activity in vivo. Gonad development and Dax1 and Sf1 expression were absent in Wt1 mutant mouse embryos. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 46,XY SEX REVERSAL 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, GLY35GLU
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<br />
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SNP: rs121918654,
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ClinVar: RCV000013638
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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>As the cause of XY sex reversal and adrenal failure in a phenotypically female patient (SRXY3; 612965), Achermann et al. (1999) found a heterozygous 2-bp GGC-to-GAA (glycine-to-glutamic acid; G35E) mutation in exon 3 of the NR5A1 gene. The mutated glycine is the last amino acid in the proximal box (P-box) of the first zinc finger of SF1. This region is critical for the recognition of DNA binding sites and confers specificity to nuclear receptors in the regulation of target genes. </p><p>Using mouse and rat constructs, Tremblay and Viger (2003) found that the SF1 G35E mutant bound the promoter region of the MIS gene (AMH; 600957) and interacted normally with its protein coactivator, GATA4 (600576), but that it failed to cooperate with GATA4 to activate the MIS reporter gene. Moreover, SF1 G35E functioned as a dominant-negative competitor and disrupted transcriptional synergism between wildtype SF1 and GATA4. </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 ADRENAL INSUFFICIENCY, NR5A1-RELATED</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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NR5A1, ARG255LEU
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<br />
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SNP: rs104894118,
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gnomAD: rs104894118,
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ClinVar: RCV000013639
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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>Biason-Lauber and Schoenle (2000) described a phenotypically normal girl who presented at age 14 months with adrenal insufficiency and no apparent defect in ovarian maturation (see 612964). The authors identified a heterozygous G-to-T transversion in exon 4 of the NR5A1 gene, leading to an arg255-to-leu (R255L) mutation in the hinge region of the NR5A1 protein. There was no evidence of mosaicism. </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 46,XY SEX REVERSAL 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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46,XX SEX REVERSAL 4, INCLUDED<br />
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ADRENAL INSUFFICIENCY, NR5A1-RELATED, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, ARG92GLN
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<br />
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SNP: rs104894119,
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ClinVar: RCV000013640, RCV000490544, RCV000490549
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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 />
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<p><strong><em>46,XY Sex Reversal 3</em></strong></p><p>
|
|
In an infant with adrenal failure and complete 46,XY sex reversal (SRXY3; 612965), Achermann et al. (2002) reported a homozygous G-to-A transition in exon 4 of the NR5A1 gene, which resulted in an arg92-to-gln (R92Q) amino acid change. This mutation altered a highly conserved residue of the A box, a region that functions as a secondary DNA binding domain. Three relatives of the infant (parents and a sister) were phenotypically normal despite being heterozygous for the mutation. In functional assays, the R92Q mutant exhibited partial loss of DNA binding and transcriptional activity when compared with the G35E P-box change (184757.0001), consistent with its phenotypic expression only when transmitted as a homozygous trait. </p><p><strong><em>46,XX Sex Reversal 4</em></strong></p><p>
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|
Swartz et al. (2017) reported a 46,XX individual of European ancestry with ambiguous genitalia, including significant clitoromegaly and rugated labia majora (SRXX4; 617480). Ultrasound and MRI showed a small uterus and abdominal gonads that were revealed to be ovotestes bilaterally by histologic analysis. The patient carried a heterozygous R92Q mutation, inherited from her unaffected father. </p><p><strong><em>NR5A1-related Adrenal Insufficiency</em></strong></p><p>
|
|
In a 2-week-old girl with primary adrenal insufficiency (see 612964) who presented with hyperpigmentation, salt-wasting crisis, prolonged jaundice, hypoglycemia, and vomiting, Guran et al. (2016) detected homozygosity for a R92Q substitution in NR5A1. The karyotype was 46,XX with a normal female phenotype. The family was reported as nonconsanguineous, and the mode of inheritance sporadic. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 46,XY SEX REVERSAL 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, 8-BP DEL, NT1058
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<br />
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ClinVar: RCV000013641
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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>Correa et al. (2004) reported a novel 8-bp microdeletion of SF1, isolated from a 46,XY patient who presented with gonadal agenesis but normal adrenal function (SRXY3; 612965), that causes premature termination upstream of sequences encoding the activation function-2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wildtype protein in most cell types. The authors stated that this was the first example of an apparent dominant-negative effect of an SF1 mutation in humans. The authors concluded that these findings, which defined an SF1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to patients who present with 46,XY sex reversal but normal adrenal functions. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 46,XY SEX REVERSAL 3</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, CYS16TER
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<br />
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SNP: rs104894123,
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gnomAD: rs104894123,
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ClinVar: RCV000013642
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 46,XY patient showing gonadal dysgenesis with normal adrenal function (SRXY3; 612965), Mallet et al. (2004) reported a heterozygous SF1 gene mutation, a C-to-A transversion in exon 2 that replaced cys16 with a stop codon (C16X). The patient showed low basal levels of anti-mullerian hormone (600957) and testosterone (T), weak T response to chorionic gonadotropin (see 118860), and hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation caused premature termination of translation and should abolish all SF1 activity; therefore, haploinsufficiency could explain the deleterious effect of this mutation, suggesting that testis development is more SF1 dose-dependent than adrenal development. The authors concluded that heterozygous mutation can impair adrenal development only if the 2 mechanisms, gene dosage and dominant-negative effects, occur. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 46,XY SEX REVERSAL 3</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, 1-BP DEL, 18C
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<br />
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SNP: rs606231205,
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ClinVar: RCV000013643
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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>Hasegawa et al. (2004) identified an SF1 mutation in a 27-year-old Japanese patient with a 46,XY karyotype and complete gonadal dysgenesis (SRXY3; 612965). Sequence analysis of all 7 exons of SF1 revealed a heterozygous 1-bp deletion at exon 2, 18delC, that was predicted to cause a frameshift at codon 6 and result in termination at codon 74 (Asp6fsTer74). Western blot analysis demonstrated no evidence of an amino-truncated SF1 protein despite the 18delC mutation being very close to the natural translation start codon. Transcription analysis indicated that the mutant was transcriptionally inactive and had no dominant-negative effect. Clinical features included small dysgenetic testes with vasa deferentia and epididymides, absent uterus, blind-ending vagina, and clitoromegaly. The authors concluded that SF1 haploinsufficiency can selectively impair testicular development and permit the biosynthesis of AMH (600957) and testosterone in dysgenetic testes and the production of gonadotropins in pituitary gonadotropes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 46,XY SEX REVERSAL 3</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, VAL15MET
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<br />
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SNP: rs104894124,
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ClinVar: RCV000013644
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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 British Caucasian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a de novo val15-to-met (V15M) substitution at a highly conserved residue in the first zinc finger of the DNA-binding domain of SF1. The baby was born with female external genitalia, and bilateral gonads (testes) were palpable in rugose labia. Endocrine studies were consistent with gonadal dysgenesis with impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the baby was raised female. Neither parent carried the mutation. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, MET78ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104894125,
|
|
|
|
|
|
|
|
ClinVar: RCV000013645
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a met78-to-ile (M78I) substitution in a highly conserved region of SF1 between the DNA-binding zinc fingers and the A-box region. The baby was born with normal female external genitalia, and bilateral gonads (testes) were detectable on deep inguinal palpation. Endocrine investigation showed poor testosterone response to human chorionic gonadotropin stimulation, very low mullerian inhibiting substance, and normal adrenal steroids; the patient underwent gonadectomy at 7 months of age. The mother carried the M78I mutation. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, GLY91SER
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|
<br />
|
|
|
|
SNP: rs104894126,
|
|
|
|
|
|
|
|
ClinVar: RCV000013646
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Fijian patient with a 46,XY disorder of sex development and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a gly91-to-ser (G91S) substitution in the A-box region of SF1. At birth, clitoral enlargement and a single perineal opening were noted; gonads (testes) were palpable in the labioscrotal folds. Endocrine studies were consistent with gonadal dysgenesis/impaired androgen biosynthesis. Gonadectomy was performed at 4 months of age and the child was raised female. The mother carried the G91S mutation. See 184757.0007 and Lin et al. (2007). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, LEU437GLN
|
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|
|
<br />
|
|
|
|
SNP: rs104894120,
|
|
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|
|
|
|
ClinVar: RCV000013647
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a British Caucasian patient with a 46,XY disorder of sex development (DSD) and normal adrenal function (SRXY3; 612965), Lin et al. (2007) identified heterozygosity for a de novo leu437-to-gln (L437Q) substitution at a highly conserved residue in the ligand-binding domain of SF1, predicted from the crystal structure to form part of the phospholipid-binding pocket. At birth, a small phallus with severe penoscrotal hypospadias and chordee but moderate corporal tissue were noted; bilateral testes were palpable and could be brought down into the scrotum, although bilateral orchipexy was required at age 6 years. Endocrine studies were consistent with impaired androgen biosynthesis. Evaluation of the hypothalamo-pituitary-gonadal axis in late childhood suggested a partial form of hypogonadotropic hypogonadism in addition to a primary testicular defect, and he required supplemental testosterone to induce puberty. Lin et al. (2007) stated that this was the first reported case of a mild phenotype in a patient raised male, and noted that the L437Q mutant retained partial function in several SF1-expressing cell lines. In contrast, the patient's testicular biopsy at 6 years of age showed more marked changes than those seen in 3 46,XY DSD patients with mutations in the NR5A1 gene (184757.0007-184757.0009) who underwent gonadectomy in infancy. </p>
|
|
</span>
|
|
</div>
|
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|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PREMATURE OVARIAN FAILURE 7, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, 1-BP DEL, 666C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs606231206,
|
|
|
|
|
|
gnomAD: rs606231206,
|
|
|
|
|
|
ClinVar: RCV000013648, RCV000013649
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lourenco et al. (2009) reported a 17-year-old female with primary amenorrhea who was diagnosed with 46,XY complete gonadal dysgenesis (SRXY3; 612965). Her mother had a history of irregular menstrual cycles and had become pregnant at the age of 23 years. After giving birth, she had anovulatory cycles that were treated for 2 years with no improvement. At age 35, she was diagnosed as 46,XX primary ovarian insufficiency (POF7; 612964). Both the mother and child were heterozygous for a frameshift mutation, 666delC, in codon 225 of the NR5A1 gene, truncating the protein from 461 to 295 amino acids. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 350 control subjects of European descent. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PREMATURE OVARIAN FAILURE 7, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, ASP293ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918655,
|
|
|
|
|
|
|
|
ClinVar: RCV000013650, RCV000013651
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lourenco et al. (2009) reported an 18-year-old with primary amenorrhea and signs of virilization who was diagnosed with a 46,XY disorder of sex development (SRXY3; 612965). A sister of the proband presented at the age of 19 years with primary amenorrhea and the diagnosis of 46,XX primary ovarian insufficiency (POF7; 612964). Mutation analysis in both sibs revealed homozygosity for an 877G-A transition in the NR5A1 gene, resulting in an asp293-to-asn (D293N) substitution. The parents were first cousins. DNA and hormonal studies were performed on 5 of 8 fertile sibs of the proband; 4 of the sibs were heterozygous and a brother did not carry the mutation. Further investigation of the family revealed a female family member with 46,XY complete gonadal dysgenesis but DNA was not available for study; her parents were also first cousins. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not observed in 782 control subjects from throughout the world. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PREMATURE OVARIAN FAILURE 7, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, MET1ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918656,
|
|
|
|
|
|
|
|
ClinVar: RCV000013652, RCV000013653
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lourenco et al. (2009) reported a French child who presented at the age of 12 years with signs of virilization and was diagnosed with 46,XY partial gonadal dysgenesis (SRXY3; 612965). A sister of the proband presented at the age of 16 years with secondary amenorrhea and was diagnosed with 46,XX primary ovarian insufficiency (POF7; 612964). The mother was 46 years of age, and menstruation was reportedly normal. The 2 affected sibs and the mother carried a heterozygous 3G-A transition in the first codon of the NR5A1 gene that predicts a met1-to-ile (M1I) substitution. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. An unaffected sib and the father did not have the mutation. The mutation was not found in 350 unaffected French control subjects. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 46,XY SEX REVERSAL 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PREMATURE OVARIAN FAILURE 7, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, 1-BP DEL, 390G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs606231207,
|
|
|
|
|
|
gnomAD: rs606231207,
|
|
|
|
|
|
ClinVar: RCV000013654, RCV000013655
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lourenco et al. (2009) reported a French child with ambiguous external genitalia and a 46,XY karyotype who was diagnosed with a disorder of sex development (SRXY3; 612965) and was raised as a boy. After his birth, his mother took oral contraceptives for 2 years until she was 29 years old, after which her menstrual cycles did not reappear. Her diagnosis was 46,XX primary ovarian insufficiency (POF7; 612964). A heterozygous frameshift mutation, 390delG, was detected in the NR5A1 gene in both the proband and his mother. The mutation is predicted to create a premature termination at codon 295. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The mutation was not detected in 350 unaffected French control subjects. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 PREMATURE OVARIAN FAILURE 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, 9-BP DEL, NT691
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs606231208,
|
|
|
|
|
|
|
|
ClinVar: RCV000013656
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Lourenco et al. (2009) reported a girl of Roma origin who presented at 12.5 years with short stature and a 46,XX karyotype. She was diagnosed with ovarian failure (POF7; 612964). Analysis of the NR5A1 gene revealed a heterozygous in-frame 9-bp deletion (691_699delCTGCAGCTG) that results in the loss of 3 amino acids (leu231_leu233) in the N-terminal region of the ligand-binding domain. In silico analysis predicted a change in hydrophobicity of helix 1 of the ligand-binding domain. Functional studies indicated that the mutation substantially impaired NR5A1 transactivational activity. The deletion was not observed in 800 control alleles, including samples from 69 unaffected subjects of Roma origin and 56 unaffected subjects from an Indian Gujarati population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PREMATURE OVARIAN FAILURE 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
SPERMATOGENIC FAILURE 8, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, GLY123ALA AND PRO129LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs200163795, rs200749741,
|
|
|
|
|
|
gnomAD: rs200163795, rs200749741,
|
|
|
|
|
|
ClinVar: RCV000013657, RCV000022775, RCV001551809, RCV001582796, RCV002247684, RCV003105833, RCV003105834, RCV003454713, RCV003967675, RCV003977699
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-month-old girl of Senegalese origin who presented with hypertrophy of the clitoris, Lourenco et al. (2009) found elevated FSH, indicating ovarian insufficiency (POF7; 612964). Molecular analysis identified 2 mutations in the NR5A1 gene that occurred in cis: a 368G-C transversion resulting in a gly123-to-ala (G123A) substitution, and a 386C-T transition resulting in a pro129-to-leu (P129L) substitution. Both mutations occurred in the hinge domain of the protein. The parents were not available for study. Functional studies indicated that the mutations substantially impaired NR5A1 transactivational activity. Neither mutation was found in 479 unaffected control subjects. </p><p>In 2 Congolese men with azoospermia and 1 Tunisian man with severe oligospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for the cis-occurring G123A/P129L mutations in the NR5A1 gene. The authors noted that all of the individuals reported to carry this double mutation were of African origin, suggesting that this is likely a founder mutation. One of the men carrying this mutation was observed to have progressive loss of germ cell quantity and quality over a 2-year period. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 SPERMATOGENIC FAILURE 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, PRO131LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906690,
|
|
|
|
|
|
gnomAD: rs387906690,
|
|
|
|
|
|
ClinVar: RCV000022776
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 41-year-old Sri Lankan man with azoospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for a 392C-T transition in the NR5A1 gene, resulting in a pro131-to-leu substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated a greater than 60% reduction in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (118485) and AMH (600957), compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 SPERMATOGENIC FAILURE 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NR5A1, GLY212SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs201095702,
|
|
|
|
|
|
gnomAD: rs201095702,
|
|
|
|
|
|
ClinVar: RCV000022777
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 37-year-old French-Vietnamese man with severe oligozoospermia (SPGF8; 613957), Bashamboo et al. (2010) identified heterozygosity for a 634G-A transition in the NR5A1 gene, resulting in a gly212-to-ser (G212S) substitution within the hinge region of the protein. The mutation was not found in more than 2,100 control samples, in 370 fertile men who had fathered at least 2 children, or in 359 normospermic men. Functional studies in HEK293T cells demonstrated approximately 80% and 70% reductions in transactivation of the promoters of 2 NR5A1 target genes, CYP11A1 (118485) and AMH (600957), respectively, compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
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<span class="mim-font">
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<strong>.0019 46,XX SEX REVERSAL 4</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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46,XY SEX REVERSAL 3, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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NR5A1, ARG92TRP
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<br />
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SNP: rs886039769,
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ClinVar: RCV000256210, RCV000490553, RCV001820799, RCV001855015
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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 5 patients from 4 unrelated families with 46,XX sex reversal (SRXX4; 617480), Bashamboo et al. (2016) identified a c.274C-T transition in the NR5A1 gene that resulted in an arg-to-trp substitution at codon 92 (R92W). In 1 of these families, a sister had 46,XY sex reversal (SRXY3; 612965) due to the same variant. In 2 families, the variant was maternally inherited, in 1 it occurred as a de novo event, and in 1 family the mutation was not present in the father, but the mother was deceased and no DNA was available. The variant was absent from the dbSNP (build 138), ExAC, and 1000 Genomes Project databases, and from an internal database containing exomes of 400 individuals as well as more than 1,000 fertile controls Sanger sequenced for NR5A1. The arg92 residue in NR5A1 is evolutionarily conserved to zebrafish. </p><p>In 3 unrelated probands with 46,XX (ovo)testicular disorder of sexual development (DSD), Baetens et al. (2017) found a c.274C-T transition in exon 4 of the NR5A1 gene (c.274C-T, NM_004959.4) that resulted in an R92W substitution in the protein. Several unaffected female first-degree relatives of the probands from each of the families also carried this mutation, suggesting that this variant is weakly penetrant. A potential founder effect was suggested by haplotype analysis. The arg92 residue is highly evolutionarily conserved to zebrafish and located in the Ftz-F1 region, probably involved with DNA-binding specificity and stability. The R92W mutation was absent from the Exome Sequencing Project (ESP), ExAC, Genome of the Netherlands (GoNL), and 1000 Genomes Project databases and from an in-house exome database. </p><p>Igarashi et al. (2017) identified the R92W mutation (c.274C-T, NM_004959.4) in 2 unrelated Japanese patients with 46,XX testicular/ovotesticular DSD. The mutation was absent from the clinically normal mothers and from 200 Japanese controls. One of the fathers, who was unaffected, carried the mutation; the other father was not available for analysis. In vitro assays showed that the mutant protein was less sensitive than wildtype to NR0B1 (300473)-induced suppression on the SOX9 (608160) enhancer element. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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<strong>Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.</strong>
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Bao Lige - updated : 05/11/2022<br>Ada Hamosh - updated : 05/24/2017<br>Marla J. F. O'Neill - updated : 08/09/2016<br>Matthew B. Gross - updated : 5/2/2016<br>Patricia A. Hartz - updated : 6/3/2014<br>Marla J. F. O'Neill - updated : 5/11/2011<br>Ada Hamosh - updated : 7/28/2009<br>Ada Hamosh - updated : 7/11/2008<br>Marla J. F. O'Neill - updated : 3/24/2008<br>John A. Phillips, III - updated : 3/24/2008<br>John A. Phillips, III - updated : 1/28/2008<br>Marla J. F. O'Neill - updated : 1/28/2008<br>John A. Phillips, III - updated : 1/18/2008<br>John A. Phillips, III - updated : 12/18/2006<br>John A. Phillips, III - updated : 8/21/2006<br>Patricia A. Hartz - updated : 8/15/2006<br>John A. Phillips, III - updated : 4/4/2006<br>John A. Phillips, III - updated : 7/25/2005<br>John A. Phillips, III - updated : 10/30/2002<br>Cassandra L. Kniffin - updated : 9/10/2002<br>John A. Phillips, III - updated : 7/13/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Victor A. McKusick - updated : 12/18/2000<br>John A. Phillips, III - updated : 11/10/2000<br>Stylianos E. Antonarakis - updated : 7/2/1999<br>Victor A. McKusick - updated : 5/25/1999<br>John A. Phillips, III - updated : 4/15/1999<br>Stylianos E. Antonarakis - updated : 6/1/1998<br>Jennifer P. Macke - updated : 4/3/1997<br>Alan F. Scott - updated : 9/27/1995
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