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Entry
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- *605597 - FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605597</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605597">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div 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=ENSG00000183770;t=ENST00000648323" 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=668" 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=605597" 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=ENSG00000183770;t=ENST00000648323" 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_023067" 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_023067" 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=605597" 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=05723&isoform_id=05723_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/FOXL2" 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/12667205,12751477,13626838,33243899,38512195,62912532,62912534,62912536,68271846,68271848,68271850,116283449,2026808716,2026808718,2026808720,2026808722,2026808724,2026808726,2026808728,2026808730,2026808732,2026808734,2026808736,2026808738,2026808740,2026808742,2026808744,2582898044" 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/P58012" 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=668" 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=ENSG00000183770;t=ENST00000648323" 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=FOXL2" 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=FOXL2" 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+668" 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/FOXL2" 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:668" 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/668" 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=chr3&hgg_gene=ENST00000648323.1&hgg_start=138944224&hgg_end=138947137&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1092" 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=605597[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
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<span class="panel-title">
|
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605597[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FOXL2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000183770" 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.gwascentral.org/search?q=FOXL2" 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=FOXL2" 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="http://medgen.ugent.be/LOVD2/home.php?select_db=FOXL2" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FOXL2&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/PA28235" 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:1092" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1349428" 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/FOXL2#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:1349428" 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/668/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=668" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060512-241" 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">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=FOXL2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 715391004<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
605597
|
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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>
|
|
<span class="mim-font">
|
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FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PITUITARY FORKHEAD FACTOR, MOUSE, HOMOLOG OF; PFRK
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FOXL2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FOXL2</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/723?start=-3&limit=10&highlight=723">3q22.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:138944224-138947137&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'})">3:138,944,224-138,947,137</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
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|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=110100,110100,608996" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/723?start=-3&limit=10&highlight=723">
|
|
3q22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Blepharophimosis, epicanthus inversus, and ptosis, type 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/110100"> 110100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
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|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Blepharophimosis, epicanthus inversus, and ptosis, type 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/110100"> 110100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
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<p>Transcription factors belonging to the evolutionarily conserved forkhead box (FOX) superfamily contain a DNA-binding motif known as the forkhead box or winged-helix domain. The forkhead box domain is about 100 amino acids long and folds into a structure containing 3 N-terminal alpha helices, 3 beta strands, and 2 loop regions near the C-terminal end of the domain. In contrast with the highly conserved forkhead box domain, FOX proteins are highly divergent in other parts of their sequences. FOX proteins vary widely in their expression patterns, regulation, and physiologic functions, with roles in eye organogenesis, language acquisition, stress response, aging regulation, and tumor suppression. FOXL2 plays a crucial role in ovarian development and female fertility (summary by <a href="#3" class="mim-tip-reference" title="Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A. <strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong> Hum. Molec. Genet. 17: 3118-3127, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635577</a>] [<a href="https://doi.org/10.1093/hmg/ddn209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18635577">Benayoun et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18635577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> positionally cloned a novel putative winged helix/forkhead transcription factor gene, FOXL2, in the blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; <a href="/entry/110100">110100</a>) critical region on chromosome 3q23. Consistent with an involvement in BPES, FOXL2 was selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appeared predominantly in the ovary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Cocquet, J., Pailhoux, E., Jaubert, F., Servel, N., Xia, X., Pannetier, M., De Baere, E., Messiaen, L., Cotinot, C., Fellous, M., Veitia, R. A. <strong>Evolution and expression of FOXL2. (Letter)</strong> J. Med. Genet. 39: 916-922, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471206</a>] [<a href="https://doi.org/10.1136/jmg.39.12.916" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471206">Cocquet et al. (2002)</a> found that the FOXL2 coding region is highly conserved in human, goat, mouse, and pufferfish. They showed that the number of alanine residues is strictly conserved among the mammals studied, suggesting the existence of strong functional or structural constraints. They provided immunohistochemical evidence indicating that FOXL2 is a nuclear protein specifically expressed in eyelids and in fetal and adult ovarian follicular cells. It does not undergo any major posttranslational maturation. They pointed out that FOXL2 is the earliest known marker of ovarian differentiation in mammals and may play a role in ovarian somatic cell differentiation and in further follicle development and/or maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471206" 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="#34" class="mim-tip-reference" title="Udar, N., Yellore, V., Chalukya, M., Yelchits, S., Silva-Garcia, R., BPES Consortium, Small, K. <strong>Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.</strong> Hum. Mutat. 22: 222-228, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12938087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12938087</a>] [<a href="https://doi.org/10.1002/humu.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12938087">Udar et al. (2003)</a> sequenced the mouse homolog for the FOXL2 gene and identified the Fugu rubripes (pufferfish) ortholog by screening the Joint Genome Institute database (<a href="#1" class="mim-tip-reference" title="Aparicio, S., Chapman, J., Stupka, E., Putnam, N., Chia, J., Dehal, P., Christoffels, A., Rash, S., Hoon, S., Smit, A., Gelpke, M. D. S., Roach, J., and 29 others. <strong>Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes.</strong> Science 297: 1301-1310, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142439</a>] [<a href="https://doi.org/10.1126/science.1072104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12142439">Aparicio et al., 2002</a>) with the mouse genomic sequence. By alignment of the human, mouse, and pufferfish sequences, they found an almost complete conservation of the forkhead domain in the 3 species. There is 95% and 61% conservation at the protein level between human-mouse and human-pufferfish, respectively. The polyalanine and polyproline tracts within the gene are absent in pufferfish. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12938087+12142439" 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="Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E. <strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong> Hum. Molec. Genet. 17: 2030-2038, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372316</a>] [<a href="https://doi.org/10.1093/hmg/ddn100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372316">Beysen et al. (2008)</a> stated that the 376-amino acid FOXL2 protein has a DNA-binding forkhead domain (FHD) of about 110 amino acids and a polyalanine tract of 14 residues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372316" 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="#11" class="mim-tip-reference" title="Crisponi, L., Uda, M., Deiana, M., Loi, A., Nagaraja, R., Chiappe, F., Schlessinger, D., Cao, A., Pilia, G. <strong>FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.</strong> Genomics 83: 757-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15081106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15081106</a>] [<a href="https://doi.org/10.1016/j.ygeno.2003.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15081106">Crisponi et al. (2004)</a> determined that mouse and human FOXL2 are single-exon genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15081106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> mapped the FOXL2 gene to chromosome 3q23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" 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>More than 99% of ovarian germ cells undergo atresia. <a href="#22" class="mim-tip-reference" title="Lee, K., Pisarska, M. D., Ko, J.-J., Kang, Y., Yoon, S., Ryou, S.-M., Cha, K.-Y., Bae, J. <strong>Transcriptional factor FOXL2 interacts with DP103 and induces apoptosis.</strong> Biochem. Biophys. Res. Commun. 336: 876-881, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16153597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16153597</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.08.184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16153597">Lee et al. (2005)</a> found that overexpression of human FOXL2 caused apoptosis in Chinese hamster ovary cells and in primed rat granulosa cells in a dose-dependent manner. Apoptosis was prevented by cotransfection of a baculoviral caspase inhibitor. Yeast 2-hybrid analysis revealed that FOXL2 interacted with the C-terminal domain of mouse Dp103 (DDX20; <a href="/entry/606168">606168</a>), an ATP-dependent RNA helicase. The region of Dp103 that interacted with FOXL2 lacks the helicase domain, but it also interacts with SF1 (NR5A1; <a href="/entry/184757">184757</a>), a nuclear factor involved in sex determination. Dp103 had no effect on cell viability alone, but cotransfection studies showed that Dp103 enhanced the apoptotic effect of FOXL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16153597" 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 PCR selection using a library of double-stranded DNA fragments and nuclear extracts of a mouse granulosa cell line, <a href="#3" class="mim-tip-reference" title="Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A. <strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong> Hum. Molec. Genet. 17: 3118-3127, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635577</a>] [<a href="https://doi.org/10.1093/hmg/ddn209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18635577">Benayoun et al. (2008)</a> identified a Foxl2 response element (FLRE) that differed significantly from other FOX protein-binding sites. The common 7-bp FLRE was 5-prime-GT(C/G)AAGG-3-prime, or its reverse complement. By transfecting mouse and human granulosa-like cells with artificial promoter reporters, <a href="#3" class="mim-tip-reference" title="Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A. <strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong> Hum. Molec. Genet. 17: 3118-3127, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635577</a>] [<a href="https://doi.org/10.1093/hmg/ddn209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18635577">Benayoun et al. (2008)</a> found that 4 tandem copies of FLRE resulted in higher reporter activity than 2, and that replacement of Gs with Ts in the FLRE core sequence resulted in an FLRE with lower FOXL2 affinity and weaker reporter activity. In addition, poly(A) expansion of FOXL2, notably expansion to 24 alanines (FOXL2-ala24), resulted in lower reporter activity when the reporter had fewer FLREs or when the FLRE had lower FOXL2 affinity. FOXL2-ala24 functioned in a dominant-negative fashion when coexpressed with wildtype FOXL2, but only with a reporter of low FOXL2 affinity. <a href="#3" class="mim-tip-reference" title="Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A. <strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong> Hum. Molec. Genet. 17: 3118-3127, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635577</a>] [<a href="https://doi.org/10.1093/hmg/ddn209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18635577">Benayoun et al. (2008)</a> concluded that the impact of poly(A) expansion on expression of FOXL2-dependent genes depends on both the number and specific sequences of FLREs in FOXL2-responsive promoters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18635577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Benayoun, B. A., Batista, F., Auer, J., Dipietromaria, A., L'Hote, D., De Baere, E., Veitia, R. A. <strong>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations.</strong> Hum. Molec. Genet. 18: 632-644, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19010791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19010791</a>] [<a href="https://doi.org/10.1093/hmg/ddn389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19010791">Benayoun et al. (2009)</a> showed that cell stress upregulated FOXL2 expression in an ovarian granulosa cell model. The response of FOXL2 to stress correlated with a dramatic remodeling of its posttranslational modification profile. Upon oxidative stress, there was increased recruitment of FOXL2 to several stress-response promoters, notably mitochondrial manganese superoxide dismutase, MnSOD (SOD2; <a href="/entry/147460">147460</a>). FOXL2 activity was repressed by the SIRT1 (<a href="/entry/604479">604479</a>) deacetylase. SIRT1 transcription was, in turn, directly upregulated by FOXL2, which closed a negative-feedback loop. Treatment with the sirtuin inhibitor nicotinamide increased FOXL2 transcription. Eleven disease-causing mutations in the ORF of FOXL2 induced aberrant regulation of FOXL2 and/or the FOXL2 stress-response target gene MnSOD. <a href="#2" class="mim-tip-reference" title="Benayoun, B. A., Batista, F., Auer, J., Dipietromaria, A., L'Hote, D., De Baere, E., Veitia, R. A. <strong>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations.</strong> Hum. Molec. Genet. 18: 632-644, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19010791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19010791</a>] [<a href="https://doi.org/10.1093/hmg/ddn389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19010791">Benayoun et al. (2009)</a> concluded that FOXL2 is an actor of the stress response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19010791" 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><strong><em>Blepharophimosis, Ptosis, and Epicanthus Inversus, Types I and II</em></strong>
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<p>There are 2 forms of the blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; <a href="/entry/110100">110100</a>). In type I, eyelid abnormalities are associated with ovarian failure. In type II, only the eyelid defects are found. <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> identified mutations in the FOXL2 gene that produced truncated proteins in type I families and larger proteins in type II families. Because of the variable phenotypes produced by mutations in forkhead transcription factor genes, <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> proposed that some mutations in the FOXL2 gene may be associated with other phenotypes, including nonsyndromic premature ovarian failure (POF; see <a href="/entry/608996">608996</a>). FOXL2 was the third forkhead gene found to be involved in the pathogenesis of inherited developmental human disorders. A single-exon gene, FOXE1 (<a href="/entry/602617">602617</a>), is mutated in cases of thyroid agenesis, and FOXC1 (<a href="/entry/601090">601090</a>) is mutated in eye defects associated with congenital glaucoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study in Korean patients, <a href="#8" class="mim-tip-reference" title="Cha, S. C., Jang, Y. S., Lee, J. H., Kim, H. K., Kim, S. C., Kim, S., Baek, S.-H., Jung, W. S., Kim, J.-R. <strong>Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong> Clin. Genet. 64: 485-490, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14986827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14986827</a>] [<a href="https://doi.org/10.1046/j.1399-0004.2003.00162.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14986827">Cha et al. (2003)</a> identified FOXL2 mutations in 5 of 9 BPES families and 3 of 7 sporadic cases. No causal mutation was found in the other BPES families or sporadic cases, suggesting that the genetic defect in some BPES patients may reside in the noncoding region of the FOXL2 gene or in other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14986827" 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="#37" class="mim-tip-reference" title="Vincent, A. L., Watkins, W. J., Sloan, B. H., Shelling, A. N. <strong>Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation.</strong> Clin. Genet. 68: 520-523, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283882</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00527.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283882">Vincent et al. (2005)</a> reported an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see <a href="/entry/126800">126800</a>), in whom they identified a heterozygous duplication of 10 alanine residues in the FOXL2 gene (<a href="#0002">605597.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an Indian cohort comprising 6 familial and 2 sporadic cases of BPES type I or type II, <a href="#20" class="mim-tip-reference" title="Kaur, I., Hussain, A., Naik, M. N., Murthy, R., Honavar, S. G. <strong>Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian blepharophimosis ptosis epicanthus inversus syndrome (BPES) patients.</strong> Brit. J. Ophthal. 95: 881-886, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21325395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21325395</a>] [<a href="https://doi.org/10.1136/bjo.2009.177972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21325395">Kaur et al. (2011)</a> identified 6 heterozygous mutations in the FOXL2 gene, 3 of which were novel (see, e.g., <a href="#0020">605597.0020</a>). In 1 family, an affected female also had polycystic ovarian disease. <a href="#20" class="mim-tip-reference" title="Kaur, I., Hussain, A., Naik, M. N., Murthy, R., Honavar, S. G. <strong>Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian blepharophimosis ptosis epicanthus inversus syndrome (BPES) patients.</strong> Brit. J. Ophthal. 95: 881-886, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21325395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21325395</a>] [<a href="https://doi.org/10.1136/bjo.2009.177972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21325395">Kaur et al. (2011)</a> noted that mutations in the region downstream of the forkhead domain were predominantly responsible for BPES among Indian patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21325395" 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><strong><em>Premature Ovarian Failure 3</em></strong>
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<div class="mim-changed mim-change"><p><a href="#18" class="mim-tip-reference" title="Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. <strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong> Molec. Hum. Reprod. 8: 729-733, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>] [<a href="https://doi.org/10.1093/molehr/8.8.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149404">Harris et al. (2002)</a> detected heterozygous FOXL2 mutations in 2 patients with isolated POF (POF3; <a href="/entry/608996">608996</a>). One mutation removed 10 of the 14 alanines in the polyalanine tract downstream of the winged helix/forkhead domain (<a href="#0016">605597.0016</a>). The other was a single-nucleotide substitution predicted to result in a tyr258-to-asn amino acid change (Y258N; <a href="#0017">605597.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149404" 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></div>
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<div class="mim-changed mim-change"><p>In a 27-year-old Tunisian patient with nonsyndromic premature ovarian failure, <a href="#21" class="mim-tip-reference" title="Laissue, P., Lakhal, B., Benayoun, B. A., Dipietromaria, A., Braham, R., Elghezal, H., Philibert, P., Saad, A., Sultan, C., Fellous, M., Veitia, R. A. <strong>Functional evidence implicating FOXL2 in nonsyndromic premature ovarian failure and in the regulation of the transcription factor OSR2.</strong> J. Med. Genet. 46: 455-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19429596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19429596</a>] [<a href="https://doi.org/10.1136/jmg.2008.065086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19429596">Laissue et al. (2009)</a> identified a heterozygous mutation in the FOXL2 gene (G187D; <a href="#0019">605597.0019</a>). Although the transactivation capacity of FOXL2-G187D was significantly lower than that of wildtype FOXL2, the mutant was able to strongly activate a reporter construct driven by the OSR2 (<a href="/entry/611297">611297</a>) promoter, believed to be a crucial target of FOXL2 in the craniofacial region. <a href="#21" class="mim-tip-reference" title="Laissue, P., Lakhal, B., Benayoun, B. A., Dipietromaria, A., Braham, R., Elghezal, H., Philibert, P., Saad, A., Sultan, C., Fellous, M., Veitia, R. A. <strong>Functional evidence implicating FOXL2 in nonsyndromic premature ovarian failure and in the regulation of the transcription factor OSR2.</strong> J. Med. Genet. 46: 455-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19429596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19429596</a>] [<a href="https://doi.org/10.1136/jmg.2008.065086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19429596">Laissue et al. (2009)</a> noted that this is compatible with the absence of BPES in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19429596" 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></div>
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<p><strong><em>Ovarian Granulosa-Cell Tumors</em></strong>
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<p><a href="#31" class="mim-tip-reference" title="Shah, S. P., Kobel, M., Senz, J., Morin, R. D., Clark, B. A., Wiegand, K. C., Leung, G., Zayed, A., Mehl, E., Kalloger, S. E., Sun, M., Giuliany, R., and 29 others. <strong>Mutation of FOXL2 in granulosa-cell tumors of the ovary.</strong> New Eng. J. Med. 360: 2719-2729, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19516027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19516027</a>] [<a href="https://doi.org/10.1056/NEJMoa0902542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19516027">Shah et al. (2009)</a> analyzed 4 adult-type ovarian granulosa-cell tumor (GCT) specimens for GCT-specific mutations and identified a somatic point mutation, 402C-G (C134W), in the FOXL2 gene in all 4 specimens. The C134W mutation was present in 86 (97%) of 89 additional adult-type GCTs, in 3 (21%) of 14 thecomas, and in 1 (10%) of 10 juvenile-type GCTs. The mutation was absent in 49 sex cord/stromal tumors of other types and in 329 unrelated ovarian or breast tumors. <a href="#31" class="mim-tip-reference" title="Shah, S. P., Kobel, M., Senz, J., Morin, R. D., Clark, B. A., Wiegand, K. C., Leung, G., Zayed, A., Mehl, E., Kalloger, S. E., Sun, M., Giuliany, R., and 29 others. <strong>Mutation of FOXL2 in granulosa-cell tumors of the ovary.</strong> New Eng. J. Med. 360: 2719-2729, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19516027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19516027</a>] [<a href="https://doi.org/10.1056/NEJMoa0902542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19516027">Shah et al. (2009)</a> concluded that mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19516027" 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><strong><em>FOXL2 Mutation Database</em></strong>
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<p><a href="#6" class="mim-tip-reference" title="Beysen, D., Vandesompele, J., Messiaen, L., De Paepe, A., De Baere, E. <strong>The human FOXL2 mutation database.</strong> Hum. Mutat. 24: 189-193, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15300845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15300845</a>] [<a href="https://doi.org/10.1002/humu.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15300845">Beysen et al. (2004)</a> described a locus-specific human FOXL2 mutation database available on the Internet. The database contained approximately 135 intragenic mutations and variants of FOXL2, but did not include variants residing outside the coding region of FOXL2 or molecular cytogenetic rearrangements of the FOXL2 locus. <a href="#6" class="mim-tip-reference" title="Beysen, D., Vandesompele, J., Messiaen, L., De Paepe, A., De Baere, E. <strong>The human FOXL2 mutation database.</strong> Hum. Mutat. 24: 189-193, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15300845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15300845</a>] [<a href="https://doi.org/10.1002/humu.20079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15300845">Beysen et al. (2004)</a> stated that at least 1 mutation in the FOXL2 gene with a putative pathogenic effect had been found in patients affected with isolated primary ovarian failure (<a href="#18" class="mim-tip-reference" title="Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. <strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong> Molec. Hum. Reprod. 8: 729-733, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>] [<a href="https://doi.org/10.1093/molehr/8.8.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149404">Harris et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12149404+15300845" 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><strong><em>Pathogenic Effects of FOXL2 Mutations</em></strong>
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<p><a href="#24" class="mim-tip-reference" title="Moumne, L., Fellous, M., Veitia, R. A. <strong>Deletions in the polyalanine-containing transcription factor FOXL2 lead to intranuclear aggregation.</strong> Hum. Molec. Genet. 14: 3557-3564, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16219626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16219626</a>] [<a href="https://doi.org/10.1093/hmg/ddi383" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16219626">Moumne et al. (2005)</a> showed that premature stop codons in the FOXL2 gene (e.g., <a href="#0008">605597.0008</a>) may lead to the production of N-terminally truncated proteins by reinitiation of translation downstream of the stop codon. Truncated proteins strongly aggregated in the nucleus, partially localized in the cytoplasm, and retained a fraction of the wildtype protein. A complete deletion of the polyalanine tract of FOXL2 induced significant intranuclear aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16219626" 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="Moumne, L., Dipietromaria, A., Batista, F., Kocer, A., Fellous, M., Pailhoux, E., Veitia, R. A. <strong>Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development.</strong> Hum. Molec. Genet. 17: 1010-1019, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158309</a>] [<a href="https://doi.org/10.1093/hmg/ddm373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158309">Moumne et al. (2008)</a> noted that polyalanine expansions of +10 residues (i.e., 24 alanines) in FOXL2 have been identified in approximately 30% of BPES patients and are mainly responsible for BPES type II. By transfecting COS-7 and KGN cells with a series of FOXL2 polyalanine variants, <a href="#23" class="mim-tip-reference" title="Moumne, L., Dipietromaria, A., Batista, F., Kocer, A., Fellous, M., Pailhoux, E., Veitia, R. A. <strong>Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development.</strong> Hum. Molec. Genet. 17: 1010-1019, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158309</a>] [<a href="https://doi.org/10.1093/hmg/ddm373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158309">Moumne et al. (2008)</a> found that the wildtype allele with 14 alanines was expressed exclusively in the nucleus. Cytoplasmic staining became statistically significant for FOXL2 containing 19 alanines, and it reached 100% for 37 alanines. FOXL2 proteins with 24 alanines or more showed aggregation in both nuclear and cytoplasmic compartments. FRAP analysis showed that wildtype FOXL2 was highly mobile within the nuclear compartment, while FOXL2 with 17 alanines showed reduced mobility, and FOXL2 with 19 alanines was virtually immobile. Reporter gene assays using the promoter regions of several FOXL2 target genes showed that alanine expansion had variable effects on promoter activity. <a href="#23" class="mim-tip-reference" title="Moumne, L., Dipietromaria, A., Batista, F., Kocer, A., Fellous, M., Pailhoux, E., Veitia, R. A. <strong>Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development.</strong> Hum. Molec. Genet. 17: 1010-1019, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18158309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18158309</a>] [<a href="https://doi.org/10.1093/hmg/ddm373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18158309">Moumne et al. (2008)</a> suggested that promoters with more FOXL2-binding sites or higher FOXL2 affinity would be less sensitive than other promoters to reduced FOXL2 availability due to protein aggregation or mislocalization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18158309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By expression in COS-7 and KGN cells, <a href="#4" class="mim-tip-reference" title="Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E. <strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong> Hum. Molec. Genet. 17: 2030-2038, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372316</a>] [<a href="https://doi.org/10.1093/hmg/ddn100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372316">Beysen et al. (2008)</a> examined the consequences of 16 missense mutations within the DNA-binding FHD of FOXL2 and another mutation outside the FHD. The mutations had variable effects on subcellular localization, aggregation, and transactivation of a reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372316" 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="#15" class="mim-tip-reference" title="Dipietromaria, A., Benayoun, B. A., Todeschini, A.-L., Rivals, I., Bazin, C., Veitia, R. A. <strong>Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems.</strong> Hum. Molec. Genet. 18: 3324-3333, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515849</a>] [<a href="https://doi.org/10.1093/hmg/ddp273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515849">Dipietromaria et al. (2009)</a> dissected the molecular and functional effects of 10 FOXL2 mutants, known to induce BPES with or without premature ovarian failure (POF). There was a correlation between the transcriptional activity of FOXL2 variants on 2 different reporter promoter assays (4XFLRE-luc and SIRT1-luc) and the type of BPES. Application of this functional framework to 18 BPES missense mutations allowed classification as type I or II mutation based on transactivation abilities. They also found a loose correlation between intranuclear aggregation and cytoplasmic mislocalization of mutant FOXL2 and the type of BPES. <a href="#15" class="mim-tip-reference" title="Dipietromaria, A., Benayoun, B. A., Todeschini, A.-L., Rivals, I., Bazin, C., Veitia, R. A. <strong>Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems.</strong> Hum. Molec. Genet. 18: 3324-3333, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515849</a>] [<a href="https://doi.org/10.1093/hmg/ddp273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515849">Dipietromaria et al. (2009)</a> suggested that a FOXL2 mutant completely lacking activity on the 2 reporter assays used in this study is likely to lead to BPES with POF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515849" 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="#13" class="mim-tip-reference" title="De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others. <strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong> Hum. Molec. Genet. 10: 1591-1600, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468277</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468277">De Baere et al. (2001)</a> identified FOXL2 mutations in 21 of 34 patients with BPES types I and II. A genotype-phenotype correlation was evident, wherein mutations predicted to result in a truncated protein either lacking or containing the forkhead domain led to BPES type I. In contrast, duplications within or downstream of the forkhead domain and a frameshift downstream of them, all predicted to result in an extended protein, caused BPES type II. In 30 unrelated patients with isolated premature ovarian failure, no causal mutations were identified in FOXL2. The initial association of BPES type I and mutations in the FOXL2 gene raised the question of whether mutations in FOXL2 could lead to isolated POF (<a href="#29" class="mim-tip-reference" title="Prueitt, R. L., Zinn, A. R. <strong>A fork in the road to fertility.</strong> Nature Genet. 27: 132-135, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175772</a>] [<a href="https://doi.org/10.1038/84735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175772">Prueitt and Zinn, 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11468277+11175772" 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="De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others. <strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 72: 478-487, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>] [<a href="https://doi.org/10.1086/346118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529855">De Baere et al. (2003)</a> described 21 FOXL2 mutations, 16 of which were novel, and stated that 53 mutations in the FOXL2 had been reported. Two mutation hotspots were identified: 30% of FOXL2 mutations led to polyalanine expansions, and 13% were novel out-of-frame duplications. They demonstrated intra- and interfamilial phenotypic variability, with both BPES types caused by the same mutation (see <a href="#0006">605597.0006</a> and <a href="#0009">605597.0009</a>). They found exceptions to their previously constructed genotype-phenotype correlation, which required revision. They assumed that for predicted proteins with a truncation before the polyalanine tract, the risk for development of POF was high. For mutations leading to a truncated or extended protein containing an intact forkhead and polyalanine tract, no predictions were possible, because some of these mutations led to both types of BPES, even within the same family. Polyalanine expansions may lead to BPES type II (see <a href="#0010">605597.0010</a>). For missense mutations, no correlations could be made. Microdeletions were associated with mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529855" 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="#7" class="mim-tip-reference" title="Boccone, L., Meloni, A., Falchi, A. M., Usai, V., Cao, A. <strong>Blepharophimosis, ptosis, epicanthus inversus syndrome, a new case associated with de novo balanced autosomal translocation [46,XY,t(3;7)(q23;q32)].</strong> Am. J. Med. Genet. 51: 258-259, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8074155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8074155</a>] [<a href="https://doi.org/10.1002/ajmg.1320510317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8074155">Boccone et al. (1994)</a> described a de novo, apparently balanced, reciprocal translocation between the long arms of chromosomes 3 and 7 in a 2-year-old male with BPES; the breakpoints were 3q23 and 7q32. <a href="#11" class="mim-tip-reference" title="Crisponi, L., Uda, M., Deiana, M., Loi, A., Nagaraja, R., Chiappe, F., Schlessinger, D., Cao, A., Pilia, G. <strong>FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.</strong> Genomics 83: 757-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15081106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15081106</a>] [<a href="https://doi.org/10.1016/j.ygeno.2003.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15081106">Crisponi et al. (2004)</a> found that the chromosome 3 breakpoint in this patient was located about 170 kb upstream of the FOXL2 gene, within exon 6 of the MRPS22 gene (<a href="/entry/605810">605810</a>), which is transcribed in the opposite orientation. They identified regions within introns 6, 11, and 12 of the MRPS22 gene that may regulate FOXL2 expression, including a winged-helix transcription factor-binding site in intron 11. <a href="#11" class="mim-tip-reference" title="Crisponi, L., Uda, M., Deiana, M., Loi, A., Nagaraja, R., Chiappe, F., Schlessinger, D., Cao, A., Pilia, G. <strong>FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.</strong> Genomics 83: 757-764, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15081106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15081106</a>] [<a href="https://doi.org/10.1016/j.ygeno.2003.11.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15081106">Crisponi et al. (2004)</a> reviewed other examples of distant defects that alter gene function, including a translocation 120 kb from the FOXC2 (<a href="/entry/602402">602402</a>) gene that causes lymphedema-distichiasis syndrome (<a href="/entry/153400">153400</a>) and a translocation more than 150 kb from the PAX6 gene (<a href="/entry/607108">607108</a>) that causes aniridia (<a href="/entry/106210">106210</a>). They suggested several models for long-range regulation of FOXL2 gene expression, including higher order genome structures that bring distant regulatory sequences within proximity of gene transcription start sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8074155+15081106" 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 sporadic patients and 2 families with BPES, <a href="#5" class="mim-tip-reference" title="Beysen, D., Raes, J., Leroy, B. P, Lucassen, A., Yates, J. R. W., Clayton-Smith, J., Ilyina, H., Sklower Brooks, S., Christin-Maitre, S., Fellous, M., Fryns, J. P., Kim, J. R., and 11 others. <strong>Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.</strong> Am. J. Hum. Genet. 77: 205-218, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15962237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15962237</a>] [<a href="https://doi.org/10.1086/432083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15962237">Beysen et al. (2005)</a> identified 4 overlapping extragenic microdeletions, ranging from 126 kb to 1.9 Mb in size, 230 kb upstream of the FOXL2 gene. The shortest region of deletion overlap contains several conserved nongenic sequences harboring putative transcription factor-binding sites and representing potential long-range cis-regulatory elements. In another family with BPES, <a href="#5" class="mim-tip-reference" title="Beysen, D., Raes, J., Leroy, B. P, Lucassen, A., Yates, J. R. W., Clayton-Smith, J., Ilyina, H., Sklower Brooks, S., Christin-Maitre, S., Fellous, M., Fryns, J. P., Kim, J. R., and 11 others. <strong>Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.</strong> Am. J. Hum. Genet. 77: 205-218, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15962237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15962237</a>] [<a href="https://doi.org/10.1086/432083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15962237">Beysen et al. (2005)</a> identified an approximately 188-kb microdeletion downstream of the FOXL2 gene. The father of the 2 affected half-sisters was unaffected, suggestive of germinal mosaicism; quantitative analysis using 3 SNPs located in the deletion showed that about 10% of paternal germ cells and 5% of somatic peripheral blood lymphocytes carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15962237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> pointed out that polled/intersex syndrome (PIS) in the goat has been suggested to be an animal model of human BPES (<a href="#36" class="mim-tip-reference" title="Vaiman, D., Schibler, L., Oustry-Vaiman, A., Pailhoux, E., Goldammer, T., Stevanovic, M., Furet, J.-P., Schwerin, M., Cotinot, C., Fellous, M., Cribiu, E. P. <strong>High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23.</strong> Genomics 56: 31-39, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10036183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10036183</a>] [<a href="https://doi.org/10.1006/geno.1998.5691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10036183">Vaiman et al., 1999</a>). It maps to 1q31 in the goat, a region homologous to human 3q23. Thus, the authors hypothesized that the goat FOXL2 gene may be the site of the mutation causing PIS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10036183+11175783" 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="Pailhoux, E., Vigier, B., Chaffaux, S., Servel, N., Taourit, S., Furet, J.-P., Fellos, M., Grosclaude, F., Cribiu, E. P., Cotinot, C., Vaiman, D. <strong>A 11.7-kb deletion triggers intersexuality and polledness in goats.</strong> Nature Genet. 29: 453-458, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726932</a>] [<a href="https://doi.org/10.1038/ng769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11726932">Pailhoux et al. (2001)</a> found by a positional cloning approach that the mutation underlying PIS in the goat is the deletion of a critical 11.7-kb DNA element containing mainly repetitive sequences. This deletion was shown to affect the transcription of at least 2 genes: PISRT1, encoding a 1.5-kb mRNA devoid of open reading frame, and FOXL2. These 2 genes are located 20 and 200 kb telomeric from the deletion, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Uda, M., Ottolenghi, C., Crisponi, L., Garcia, J. E., Deiana, M., Kimber, W., Forabosco, A., Cao, A., Schlessinger, D., Pilia, G. <strong>Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.</strong> Hum. Molec. Genet. 13: 1171-1181, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056605</a>] [<a href="https://doi.org/10.1093/hmg/ddh124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15056605">Uda et al. (2004)</a> reported that mice lacking Foxl2 recapitulated relevant features of human BPES: males and females were small and showed distinctive craniofacial morphology with absent upper eyelids. Furthermore, in mice as in humans, sterility was confined to females: all major somatic cell lineages failed to develop around growing oocytes from the time of primordial follicle formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056605" 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="Ottolenghi, C., Omari, S., Garcia-Ortiz, J. E., Uda, M., Crisponi, L., Forabosco, A., Pilia, G., Schlessinger, D. <strong>Foxl2 is required for commitment to ovary differentiation.</strong> Hum. Molec. Genet. 14: 2053-2062, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15944199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15944199</a>] [<a href="https://doi.org/10.1093/hmg/ddi210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15944199">Ottolenghi et al. (2005)</a> found that mouse XX gonads lacking Foxl2 formed meiotic prophase oocytes, but then activated the genetic program for somatic testis determination. Pivotal Foxl2 action repressed the male gene pathway at several stages of female gonadal differentiation. The authors proposed a continued involvement of sex-determining genes in maintaining ovarian function throughout female reproductive life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15944199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Ottolenghi, C., Pelosi, E., Tran, J., Colombino, M., Douglass, E., Nedorezov, T., Cao, A., Forabosco, A., Schlessinger, D. <strong>Loss of Wnt4 and Fox12 leads to female-to-male sex reversal extending to germ cells.</strong> Hum. Molec. Genet. 16: 2795-2804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17728319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17728319</a>] [<a href="https://doi.org/10.1093/hmg/ddm235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17728319">Ottolenghi et al. (2007)</a> observed formation of testis-like tubules and spermatogonia in the ovaries of Wnt4/Foxl2 double-knockout XX mice, demonstrating that female sex-determining genes, the putative 'ovary organizer,' are required to suppress an alternative male fate in the ovary and act as a female equivalent of SRY (<a href="/entry/480000">480000</a>). Forced expression of Foxl2 impaired testis tubule differentiation in XY transgenic mice, and germ cell-depleted XX mice lacking Foxl2 and harboring a Kit (<a href="/entry/164920">164920</a>) mutation underwent partial female-to-male sex reversal. <a href="#27" class="mim-tip-reference" title="Ottolenghi, C., Pelosi, E., Tran, J., Colombino, M., Douglass, E., Nedorezov, T., Cao, A., Forabosco, A., Schlessinger, D. <strong>Loss of Wnt4 and Fox12 leads to female-to-male sex reversal extending to germ cells.</strong> Hum. Molec. Genet. 16: 2795-2804, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17728319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17728319</a>] [<a href="https://doi.org/10.1093/hmg/ddm235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17728319">Ottolenghi et al. (2007)</a> stated that the results were all consistent with an anti-testis role for FOXL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17728319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Uhlenhaut, N. H., Jakob, S., Anlag, K., Eisenberger, T., Sekido, R., Kress, J., Treier, A.-C., Klugmann, C., Klasen, C., Holter, N. I., Riethmacher, D., Schutz, G., Cooney, A. J., Lovell-Badge, R., Treier, M. <strong>Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.</strong> Cell 139: 1130-1142, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20005806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20005806</a>] [<a href="https://doi.org/10.1016/j.cell.2009.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20005806">Uhlenhaut et al. (2009)</a> found that Foxl2 was required to prevent transdifferentiation of an adult mouse ovary to a testis. Foxl2 repressed testis differentiation in vivo mainly through repression of the Sox9 (<a href="/entry/608160">608160</a>) cis-regulatory sequence TESCO. Foxl2 and estrogen receptor (ESR1; <a href="/entry/133430">133430</a>) cooperated in Sox9 repression in vivo, thus providing a mechanism by which loss of estrogen signaling could lead to gonadal sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20005806" 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 piggyBac (PB) insertional mutagenesis, <a href="#32" class="mim-tip-reference" title="Shi, F., Ding, S., Zhao, S., Han, M., Zhuang, Y., Xu, T., Wu, X. <strong>A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice.</strong> Hum. Molec. Genet. 23: 3792-3800, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24565867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24565867</a>] [<a href="https://doi.org/10.1093/hmg/ddu092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24565867">Shi et al. (2014)</a> created a line of mice with a modest yet significant reduction in Foxl2 expression and a BPES-like phenotype. Homozygous PB/PB mice began to lose weight approximately 2 weeks after birth, and most died within the first month of life. At 3 weeks of age, they showed significant overgrowth of mandibular incisors with malocclusion, and some showed palpebral anomalies and periocular hair loss. Surviving female PB/PB mice were subfertile, with smaller than normal ovaries and uteri. <a href="#32" class="mim-tip-reference" title="Shi, F., Ding, S., Zhao, S., Han, M., Zhuang, Y., Xu, T., Wu, X. <strong>A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice.</strong> Hum. Molec. Genet. 23: 3792-3800, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24565867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24565867</a>] [<a href="https://doi.org/10.1093/hmg/ddu092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24565867">Shi et al. (2014)</a> mapped the PB insertion site to a region approximately 160 kb upstream of the Foxl2 transcription start site and approximately 10 kb upstream of an element, ECF1, that showed a high degree of conservation among goat, mouse, and human. ECF1 functioned as an enhancer in reporter gene assays and interacted directly with the Foxl2 promoter in chromosome conformation capture assays. <a href="#32" class="mim-tip-reference" title="Shi, F., Ding, S., Zhao, S., Han, M., Zhuang, Y., Xu, T., Wu, X. <strong>A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice.</strong> Hum. Molec. Genet. 23: 3792-3800, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24565867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24565867</a>] [<a href="https://doi.org/10.1093/hmg/ddu092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24565867">Shi et al. (2014)</a> noted that BPES patients with balanced translocations and chromosome breakpoints 130, 160, or 171 kb upstream of FOXL2 have been reported. The authors hypothesized that these translocations may isolate transcription regulatory elements, including the human ECF1 ortholog, leading to FOXL2 misregulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24565867" 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="mim-changed mim-change"><p>In a family with type I BPES (<a href="/entry/110100">110100</a>), <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> found that affected members had a C-to-T transition at position c.892, resulting in a codon that predicted a truncated protein (gln219 to ter). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" 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></div>
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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> rs387906321 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906321;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/rs387906321?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=rs387906321" 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=rs387906321" 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=RCV000005127 OR RCV000005128 OR RCV000408801 OR RCV002512795" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005127, RCV000005128, RCV000408801, RCV002512795" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005127...</a>
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<div class="mim-changed mim-change"><p>In affected members of 2 families with BPES type II (<a href="/entry/110100">110100</a>), and in a sporadic male BPES patient, <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> identified a 30-bp duplication at position 909 to 938 (c.909_938dup). Amino acids 224 to 234 were duplicated. In the 2 families with multiple cases, affected females transmitted the trait to the next generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" 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></div>
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<p><a href="#30" class="mim-tip-reference" title="Ramirez-Castro, J. L., Pineda-Trujillo, N., Valencia, A. V., Muneton, C. M., Botero, O., Trujillo, O., Vasquez, G., Mora, B. E., Durango, N., Bedoya, G., Ruiz-Linares, A. <strong>Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.</strong> Am. J. Med. Genet. 113: 47-51, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12400065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12400065</a>] [<a href="https://doi.org/10.1002/ajmg.10741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12400065">Ramirez-Castro et al. (2002)</a> identified this mutation in affected members of 2 families with BPES type II from a historically isolated population in northwest Colombia. The genotype/phenotype correlation in the families was consistent with a proposal that BPES type I is caused by truncating mutations leading to haploinsufficiency, while BPES type II is caused by mutations generating elongated protein products (see also <a href="#0008">605597.0008</a>). This duplication has also been described as recurrent in unrelated familial and sporadic BPES cases in Europe; its recurrence may be related to the secondary structure of the particular DNA region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12400065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In both a family and sporadic case of BPES type II from Algeria, <a href="#16" class="mim-tip-reference" title="Dollfus, H., Stoetzel, C., Riehm, S., Lahlou Boukoffa, W., Bediard Boulaneb, F., Quillet, R., Abu-Eid, M., Speeg-Schatz, C., Francfort, J. J., Flament, J., Veillon, F., Perrin-Schmitt, F. <strong>Sporadic and familial blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.</strong> Clin. Genet. 63: 117-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630957</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00011.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630957">Dollfus et al. (2003)</a> identified this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see <a href="/entry/126800">126800</a>), <a href="#37" class="mim-tip-reference" title="Vincent, A. L., Watkins, W. J., Sloan, B. H., Shelling, A. N. <strong>Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation.</strong> Clin. Genet. 68: 520-523, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283882</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00527.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283882">Vincent et al. (2005)</a> identified heterozygosity for a 30-bp duplication, which they designated 672_701dup30 based on numbering from the ATG start codon, resulting in a duplication of 10 alanine residues at codon 224 in the FOXL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283882" 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 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs863225450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225450;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=rs863225450" 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=rs863225450" 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=RCV000005129" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005129" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005129</a>
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<div class="mim-changed mim-change"><p>In a family with BPES type I (<a href="/entry/110100">110100</a>), <a href="#13" class="mim-tip-reference" title="De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others. <strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong> Hum. Molec. Genet. 10: 1591-1600, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468277</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468277">De Baere et al. (2001)</a> found that affected members had a CA dinucleotide deletion from position 290 to 291 (c.290_291delCA), resulting in a frameshift generating 76 novel amino acids and terminating prematurely at codon 94. The entire forkhead domain was obliterated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468277" 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></div>
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<strong>.0004 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs863225451 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225451;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=rs863225451" 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=rs863225451" 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 family with BPES type I (<a href="/entry/110100">110100</a>), <a href="#13" class="mim-tip-reference" title="De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others. <strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong> Hum. Molec. Genet. 10: 1591-1600, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468277</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468277">De Baere et al. (2001)</a> found that affected members had an 8-bp duplication at position 1149 to 1156, resulting in a frameshift generating 50 novel amino acids and terminating prematurely at codon 358. Neither the forkhead domain nor the polyalanine tract were disrupted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468277" 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 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</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">rs863225452 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225452;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=rs863225452" 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=rs863225452" 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 family with BPES type II (<a href="/entry/110100">110100</a>), <a href="#13" class="mim-tip-reference" title="De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others. <strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong> Hum. Molec. Genet. 10: 1591-1600, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468277</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468277">De Baere et al. (2001)</a> found that affected members had a 15-bp duplication at position 415 to 429, resulting in duplication of amino acids 60 to 64 within the forkhead domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468277" 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>.0006 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs797044528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044528;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/rs797044528?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=rs797044528" 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=rs797044528" 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=RCV000005132 OR RCV000005133 OR RCV000192036 OR RCV000727228 OR RCV004619186 OR RCV004795377" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005132, RCV000005133, RCV000192036, RCV000727228, RCV004619186, RCV004795377" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005132...</a>
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<p>In 2 families with BPES II (<a href="/entry/110100">110100</a>), <a href="#13" class="mim-tip-reference" title="De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others. <strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong> Hum. Molec. Genet. 10: 1591-1600, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11468277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11468277</a>] [<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11468277">De Baere et al. (2001)</a> found that affected members had a 1-bp cytosine insertion following position 1041, resulting in 264 novel amino acids beginning at codon 268 and extending the protein from 376 amino acids to 532 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11468277" 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="De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others. <strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 72: 478-487, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>] [<a href="https://doi.org/10.1086/346118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529855">De Baere et al. (2003)</a> found this mutation in a family with BPES I. They stated that this was the first mutation shown to lead to both BPES types in different families (interfamilial phenotypic variability). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</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">rs797044532 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044532;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=rs797044532" 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=rs797044532" 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=RCV000005134 OR RCV000192041" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005134, RCV000192041" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005134...</a>
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<p>In a Japanese family with BPES type II (<a href="/entry/110100">110100</a>), <a href="#38" class="mim-tip-reference" title="Yamada, T., Hayasaka, S., Matsumoto, M., Budu, Esa, T., Hayasaka, Y., Endo, M. <strong>Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong> J. Hum. Genet. 46: 733-736, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11776388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11776388</a>] [<a href="https://doi.org/10.1007/s100380170009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11776388">Yamada et al. (2001)</a> found a heterozygous 17-bp deletion at nucleotide 1092 in the FOXL2 gene. BPES type II was suspected because the affected woman had 3 sons. Four individuals in 3 sibships in 3 generations were affected. There was 1 instance of male-to-male transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11776388" 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 17-bp duplication at nucleotide 1092 was described by <a href="#34" class="mim-tip-reference" title="Udar, N., Yellore, V., Chalukya, M., Yelchits, S., Silva-Garcia, R., BPES Consortium, Small, K. <strong>Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.</strong> Hum. Mutat. 22: 222-228, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12938087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12938087</a>] [<a href="https://doi.org/10.1002/humu.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12938087">Udar et al. (2003)</a> in 3 unrelated pedigrees, indicating that nucleotide 1092 is a hotspot; see <a href="#0014">605597.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12938087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs104893737 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893737;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=rs104893737" 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=rs104893737" 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=RCV000005135 OR RCV000760402" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005135, RCV000760402" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005135...</a>
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<div class="mim-changed mim-change"><p>In a family from a historically isolated population in northwest Colombia with BPES type I (<a href="/entry/110100">110100</a>), <a href="#30" class="mim-tip-reference" title="Ramirez-Castro, J. L., Pineda-Trujillo, N., Valencia, A. V., Muneton, C. M., Botero, O., Trujillo, O., Vasquez, G., Mora, B. E., Durango, N., Bedoya, G., Ruiz-Linares, A. <strong>Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.</strong> Am. J. Med. Genet. 113: 47-51, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12400065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12400065</a>] [<a href="https://doi.org/10.1002/ajmg.10741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12400065">Ramirez-Castro et al. (2002)</a> demonstrated linkage to chromosome 3q23 and found a novel c.394C-T mutation of the FOXL2 gene which deleted the forkhead DNA binding domain. This mutation resulted in the creation of a stop codon at position 53 (Q53X) of FOXL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12400065" 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></div>
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<p><a href="#24" class="mim-tip-reference" title="Moumne, L., Fellous, M., Veitia, R. A. <strong>Deletions in the polyalanine-containing transcription factor FOXL2 lead to intranuclear aggregation.</strong> Hum. Molec. Genet. 14: 3557-3564, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16219626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16219626</a>] [<a href="https://doi.org/10.1093/hmg/ddi383" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16219626">Moumne et al. (2005)</a> showed that the Q53X mutation could result in production of N-terminally truncated proteins by reinitiation of translation downstream of the stop codon. The Q53X fusion protein was detected by Western blot analysis as a band corresponding to initiation at codon 137 and localized to the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16219626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
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BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893738;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=rs104893738" 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=rs104893738" 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=RCV000005136 OR RCV000005137 OR RCV002496265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005136, RCV000005137, RCV002496265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005136...</a>
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<div class="mim-changed mim-change"><p><a href="#12" class="mim-tip-reference" title="De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others. <strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 72: 478-487, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>] [<a href="https://doi.org/10.1086/346118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529855">De Baere et al. (2003)</a> reported a family in which BPES (<a href="/entry/110100">110100</a>) was related to a c.1059C-G transversion in the FOXL2 gene, predicted to result in a nonsense tyr274-to-ter (Y274X) mutation. The mother was affected by BPES type II and she transmitted the disease to her daughter, who was affected by BPES type I. The latter received ovum donation at age 33 years, resulting in 1 successful pregnancy. <a href="#12" class="mim-tip-reference" title="De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others. <strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 72: 478-487, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>] [<a href="https://doi.org/10.1086/346118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529855">De Baere et al. (2003)</a> stated that this was the first reported case in which both types of BPES caused by the same mutation were documented in the same family, indicating intrafamilial phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529855" 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></div>
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<strong>.0010 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</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">rs387906322 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906322;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=rs387906322" 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=rs387906322" 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=RCV000005138 OR RCV002490318" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005138, RCV002490318" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005138...</a>
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<p>In a family with BPES type II (<a href="/entry/110100">110100</a>), <a href="#12" class="mim-tip-reference" title="De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others. <strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 72: 478-487, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>] [<a href="https://doi.org/10.1086/346118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12529855">De Baere et al. (2003)</a> found a novel in-frame 15-bp triplication of nucleotides 921-935 in the FOXL2 gene, leading to a polyalanine expansion of 5 alanine residues, 228-232. They stated that this was the first triplication observed in the polyalanine tract of FOXL2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs28937884 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937884;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=rs28937884" 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=rs28937884" 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=RCV000005139 OR RCV003894790" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005139, RCV003894790" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005139...</a>
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<p><a href="#16" class="mim-tip-reference" title="Dollfus, H., Stoetzel, C., Riehm, S., Lahlou Boukoffa, W., Bediard Boulaneb, F., Quillet, R., Abu-Eid, M., Speeg-Schatz, C., Francfort, J. J., Flament, J., Veillon, F., Perrin-Schmitt, F. <strong>Sporadic and familial blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.</strong> Clin. Genet. 63: 117-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630957</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00011.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630957">Dollfus et al. (2003)</a> studied a family originating from Strasbourg, France, that was considered to be one of the largest reported BPES type I (<a href="/entry/110100">110100</a>) families. The first reported case in this family was born in 1841 from presumed unaffected parents, and thereafter 36 affected individuals were identified over 6 generations. The affected members of the family had typical BPES features. Only males, strikingly and exclusively, transmitted the disease, as affected females were known to be infertile. A 488T-G transversion (genomic sequence numbering) in the FOXL2 gene, resulting in an ile84-to-ser (I84S) mutation, segregated with the disorder in the family. On MRI studies, the superior levator palpebrae could not be seen in 4 patients and appeared to be very thin in a fifth patient, but the other oculomotor muscles appeared to be normal on the MRI images. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908358 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908358;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/rs121908358?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=rs121908358" 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=rs121908358" 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=RCV000005140 OR RCV003231089" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005140, RCV003231089" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005140...</a>
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<p>In a 24-month-old French girl with sporadic BPES type I (<a href="/entry/110100">110100</a>), <a href="#16" class="mim-tip-reference" title="Dollfus, H., Stoetzel, C., Riehm, S., Lahlou Boukoffa, W., Bediard Boulaneb, F., Quillet, R., Abu-Eid, M., Speeg-Schatz, C., Francfort, J. J., Flament, J., Veillon, F., Perrin-Schmitt, F. <strong>Sporadic and familial blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.</strong> Clin. Genet. 63: 117-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630957</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00011.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630957">Dollfus et al. (2003)</a> identified a 532C-T transition (genomic sequence numbering) in the FOXL2 gene, resulting in a GLN98TER (Q98X) mutation. The mutation resulted in a truncated protein and was not found in her parents or 3 sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630957" 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>As indicated in the report of <a href="#4" class="mim-tip-reference" title="Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E. <strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong> Hum. Molec. Genet. 17: 2030-2038, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372316</a>] [<a href="https://doi.org/10.1093/hmg/ddn100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372316">Beysen et al. (2008)</a>, the amino acid at position 98 in FOXL2 is tryptophan. The correct nomenclature for the mutation reported by <a href="#16" class="mim-tip-reference" title="Dollfus, H., Stoetzel, C., Riehm, S., Lahlou Boukoffa, W., Bediard Boulaneb, F., Quillet, R., Abu-Eid, M., Speeg-Schatz, C., Francfort, J. J., Flament, J., Veillon, F., Perrin-Schmitt, F. <strong>Sporadic and familial blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.</strong> Clin. Genet. 63: 117-120, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630957</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00011.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12630957">Dollfus et al. (2003)</a> is gln99 to ter (Q99X), not GLN98TER. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18372316+12630957" 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>.0013 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS</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">rs104893739 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893739;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=rs104893739" 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=rs104893739" 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=RCV000005141" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005141" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005141</a>
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<div class="mim-changed mim-change"><p>In a male with BPES (<a href="/entry/110100">110100</a>), <a href="#34" class="mim-tip-reference" title="Udar, N., Yellore, V., Chalukya, M., Yelchits, S., Silva-Garcia, R., BPES Consortium, Small, K. <strong>Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.</strong> Hum. Mutat. 22: 222-228, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12938087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12938087</a>] [<a href="https://doi.org/10.1002/humu.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12938087">Udar et al. (2003)</a> found a spontaneous c.823C-T transition in the FOXL2 gene that resulted in a truncation (gln196 to ter; Q196X) of the putative protein downstream of the forkhead domain. The nucleotides and amino acid residues at this position are conserved in human, mouse, and pufferfish. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12938087" 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></div>
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<strong>.0014 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs797044532 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044532;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=rs797044532" 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=rs797044532" 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=RCV000005142 OR RCV000192040 OR RCV000599160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005142, RCV000192040, RCV000599160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005142...</a>
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<div class="mim-changed mim-change"><p>In 3 affected members of a family with BPES type I (<a href="/entry/110100">110100</a>), <a href="#10" class="mim-tip-reference" title="Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others. <strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong> Nature Genet. 27: 159-166, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>] [<a href="https://doi.org/10.1038/84781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175783">Crisponi et al. (2001)</a> reported a duplication of 17 bp at position 1092-1108 (c.1092_1108dup17), causing a frameshift resulting in a shorter protein. In a mutation search by direct sequencing in 9 affected individuals representing familial or sporadic cases, <a href="#34" class="mim-tip-reference" title="Udar, N., Yellore, V., Chalukya, M., Yelchits, S., Silva-Garcia, R., BPES Consortium, Small, K. <strong>Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.</strong> Hum. Mutat. 22: 222-228, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12938087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12938087</a>] [<a href="https://doi.org/10.1002/humu.10251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12938087">Udar et al. (2003)</a> found this mutation in 3 unrelated pedigrees. There is a proline tract at this position, and the mutation results in a His291fsTer361 frameshift. A deletion mutation involving the same 17 bases was reported in a Japanese BPES patient by <a href="#38" class="mim-tip-reference" title="Yamada, T., Hayasaka, S., Matsumoto, M., Budu, Esa, T., Hayasaka, Y., Endo, M. <strong>Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong> J. Hum. Genet. 46: 733-736, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11776388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11776388</a>] [<a href="https://doi.org/10.1007/s100380170009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11776388">Yamada et al. (2001)</a>; see (<a href="#0007">605597.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12938087+11776388+11175783" 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></div>
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<strong>.0015 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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">rs863225453 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225453;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=rs863225453" 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=rs863225453" 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=RCV000005143" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005143" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005143</a>
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<div class="mim-changed mim-change"><p>In a 32-year-old woman with sporadic BPES type I (<a href="/entry/110100">110100</a>) and a history of menstrual irregularities and periods of secondary amenorrhea, <a href="#17" class="mim-tip-reference" title="Fokstuen, S., Antonarakis, S. E., Blouin, J.-L. <strong>FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients.</strong> Am. J. Med. Genet. 117A: 143-146, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12567411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12567411</a>] [<a href="https://doi.org/10.1002/ajmg.a.10024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12567411">Fokstuen et al. (2003)</a> identified a heterozygous 1-bp insertion in the FOXL2 gene, c.959insG, resulting in 212 novel amino acids at the carboxyl end of the protein beginning at codon 321 and extending the protein from 376 to 532 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12567411" 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></div>
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<strong>.0016 PREMATURE OVARIAN FAILURE 3</strong>
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FOXL2, 30-BP DEL, NT898
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005144 OR RCV003311650" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005144, RCV003311650" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005144...</a>
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<div class="mim-changed mim-change"><p>In a 17-year-old Slovenian woman with premature ovarian failure-3 (POF3; <a href="/entry/608996">608996</a>), <a href="#18" class="mim-tip-reference" title="Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. <strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong> Molec. Hum. Reprod. 8: 729-733, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>] [<a href="https://doi.org/10.1093/molehr/8.8.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149404">Harris et al. (2002)</a> identified a heterozygous 30-bp deletion (c.898_927del) that removed 10 of the 14 alanines from a polyalanine tract downstream of the winged helix/forkhead domain of the protein (A221_A230del). The patient was identified in a screening of the FOXL2 gene in 70 patients from New Zealand and Slovenia with premature ovarian failure. The patient's mother and sister did not carry the variant; her father was deceased. <a href="#18" class="mim-tip-reference" title="Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. <strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong> Molec. Hum. Reprod. 8: 729-733, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>] [<a href="https://doi.org/10.1093/molehr/8.8.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149404">Harris et al. (2002)</a> stated that this was the first report of a deletion within a polyalanine tract being associated with a disease phenotype, although polyalanine expansions are known to be causative in several conditions; for example, in some families with BPES type II (<a href="/entry/110100">110100</a>), the polyalanine tract of FOXL2 has been shown to be expanded (<a href="#0010">605597.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149404" 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></div>
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<strong>.0017 PREMATURE OVARIAN FAILURE 3</strong>
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FOXL2, TYR258ASN
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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> rs28937885 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937885;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/rs28937885?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=rs28937885" 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=rs28937885" 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=RCV000005145 OR RCV000987342 OR RCV005089174" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005145, RCV000987342, RCV005089174" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005145...</a>
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<div class="mim-changed mim-change"><p>In a woman from New Zealand who underwent premature ovarian failure (POF3; <a href="/entry/608996">608996</a>) at the age of 38 years, <a href="#18" class="mim-tip-reference" title="Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. <strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong> Molec. Hum. Reprod. 8: 729-733, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>] [<a href="https://doi.org/10.1093/molehr/8.8.729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12149404">Harris et al. (2002)</a> identified a heterozygous c.1009T-A transversion in the FOXL2 gene, resulting in a tyr258-to-asn (Y258N) substitution. Her mother also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149404" 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></div>
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<strong>.0018 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
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FOXL2, 15-BP DUP, NT684, ALANINE TRACT EXPANSION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005146" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005146" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005146</a>
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<div class="mim-changed mim-change"><p>In 3 affected males and 1 affected female of a consanguineous Indian family with BPES type I (<a href="/entry/110100">110100</a>), <a href="#25" class="mim-tip-reference" title="Nallathambi, J., Moumne, L., De Baere, E., Beysen, D., Usha, K., Sundaresan, P., Veitia, R. A. <strong>A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.</strong> Hum. Genet. 121: 107-112, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17089161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17089161</a>] [<a href="https://doi.org/10.1007/s00439-006-0276-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17089161">Nallathambi et al. (2007)</a> identified a homozygous 15-bp duplication (c.684-698dup15), resulting in an in-frame polyalanine expansion from 14 to 19 residues (Ala19). Several unaffected relatives were heterozygous for the mutation, indicating autosomal recessive inheritance in this family. The affected 30-year-old woman had amenorrhea and impaired fertility, consistent with ovarian dysfunction. Transfection studies in COS-7 cells showed that the Ala19 mutant protein showed increased cytoplasmic retention compared to wildtype, but decreased retention compared to longer expansion mutations, consistent with Ala19 being a hypomorphic allele with residual activity. <a href="#25" class="mim-tip-reference" title="Nallathambi, J., Moumne, L., De Baere, E., Beysen, D., Usha, K., Sundaresan, P., Veitia, R. A. <strong>A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.</strong> Hum. Genet. 121: 107-112, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17089161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17089161</a>] [<a href="https://doi.org/10.1007/s00439-006-0276-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17089161">Nallathambi et al. (2007)</a> noted that Ala19 is the shortest polyalanine expansion (+5) described in the FOXL2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17089161" 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></div>
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<strong>.0019 PREMATURE OVARIAN FAILURE 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"><span class="text-primary">●</span> rs121908359 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908359;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/rs121908359?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=rs121908359" 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=rs121908359" 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=RCV000005147 OR RCV000192031 OR RCV002251877 OR RCV003546451" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005147, RCV000192031, RCV002251877, RCV003546451" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005147...</a>
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<div class="mim-changed mim-change"><p>In a 27-year-old Tunisian patient with nonsyndromic premature ovarian failure (POF3; <a href="/entry/608996">608996</a>), <a href="#21" class="mim-tip-reference" title="Laissue, P., Lakhal, B., Benayoun, B. A., Dipietromaria, A., Braham, R., Elghezal, H., Philibert, P., Saad, A., Sultan, C., Fellous, M., Veitia, R. A. <strong>Functional evidence implicating FOXL2 in nonsyndromic premature ovarian failure and in the regulation of the transcription factor OSR2.</strong> J. Med. Genet. 46: 455-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19429596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19429596</a>] [<a href="https://doi.org/10.1136/jmg.2008.065086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19429596">Laissue et al. (2009)</a> identified heterozygosity for a c.560G-A transition in the FOXL2 gene, resulting in a gly187-to-asp (G187D) substitution in a highly conserved segment, C-terminal to the forkhead domain. The paternally inherited mutation was not found in 110 control chromosomes; it had been previously detected in an XX male (<a href="#14" class="mim-tip-reference" title="De Baere, E., Lemercier, B., Christin-Maitre, S., Durval, D., Messiaen, L., Fellous, M., Veitia, R. <strong>FOXL2 mutation screening in a large panel of POF patients and XX males.</strong> J. Med. Genet. 39: e43 only, 2002. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12161610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12161610</a>] [<a href="https://doi.org/10.1136/jmg.39.8.e43" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12161610">De Baere et al., 2002</a>), but its link to that condition was unclear. Although transfection studies demonstrated normal subcellular localization of the mutant FOXL2, its transactivation capacity, which was tested on 2 reporter promoters including 1 that may be relevant to the ovary, was significantly lower than that of wildtype FOXL2. However, the G187D mutant was able to strongly activate a reporter construct driven by the OSR2 (<a href="/entry/611297">611297</a>) promoter, believed to be a crucial target of FOXL2 in the craniofacial region. <a href="#21" class="mim-tip-reference" title="Laissue, P., Lakhal, B., Benayoun, B. A., Dipietromaria, A., Braham, R., Elghezal, H., Philibert, P., Saad, A., Sultan, C., Fellous, M., Veitia, R. A. <strong>Functional evidence implicating FOXL2 in nonsyndromic premature ovarian failure and in the regulation of the transcription factor OSR2.</strong> J. Med. Genet. 46: 455-457, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19429596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19429596</a>] [<a href="https://doi.org/10.1136/jmg.2008.065086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19429596">Laissue et al. (2009)</a> noted that this is compatible with the absence of BPES in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19429596+12161610" 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></div>
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<strong>.0020 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
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FOXL2, GLU69LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906920 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906920;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=rs387906920" 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=rs387906920" 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=RCV000023464" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023464" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023464</a>
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<div class="mim-changed mim-change"><p>In a 4-generation Indian family segregating BPES type II (<a href="/entry/110100">110100</a>), <a href="#20" class="mim-tip-reference" title="Kaur, I., Hussain, A., Naik, M. N., Murthy, R., Honavar, S. G. <strong>Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian blepharophimosis ptosis epicanthus inversus syndrome (BPES) patients.</strong> Brit. J. Ophthal. 95: 881-886, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21325395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21325395</a>] [<a href="https://doi.org/10.1136/bjo.2009.177972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21325395">Kaur et al. (2011)</a> identified heterozygosity and homozygosity for a c.205G-A transition in the FOXL2 gene, resulting in a glu69-to-lys (E69K) substitution. The proband and his brother were homozygous for the mutation; both parents were heterozygous for the mutation. Their mother and a paternal aunt had classic BPES and their father had telecanthus. The disease severity in the family was found to be directly linked to the allelic dosage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21325395" 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></div>
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<p><a href="#4" class="mim-tip-reference" title="Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E. <strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong> Hum. Molec. Genet. 17: 2030-2038, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372316</a>] [<a href="https://doi.org/10.1093/hmg/ddn100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18372316">Beysen et al. (2008)</a> found that the E69K substitution resulted in massive nuclear aggregation of FOXL2 following expression in COS-7 cells. However, the mutation had no discernible effect on transactivation of a DK3-Luc reporter gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372316" 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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<br />
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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<a id="Aparicio2002" class="mim-anchor"></a>
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Aparicio, S., Chapman, J., Stupka, E., Putnam, N., Chia, J., Dehal, P., Christoffels, A., Rash, S., Hoon, S., Smit, A., Gelpke, M. D. S., Roach, J., and 29 others.
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<strong>Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12142439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12142439</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12142439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1072104" target="_blank">Full Text</a>]
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<a id="Benayoun2009" class="mim-anchor"></a>
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Benayoun, B. A., Batista, F., Auer, J., Dipietromaria, A., L'Hote, D., De Baere, E., Veitia, R. A.
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<strong>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations.</strong>
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Hum. Molec. Genet. 18: 632-644, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19010791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19010791</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19010791" 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/ddn389" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Benayoun2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A.
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<strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong>
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Hum. Molec. Genet. 17: 3118-3127, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18635577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18635577</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18635577" 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/ddn209" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Beysen2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E.
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<strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong>
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Hum. Molec. Genet. 17: 2030-2038, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18372316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18372316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18372316" 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/ddn100" target="_blank">Full Text</a>]
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<a id="Beysen2005" class="mim-anchor"></a>
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Beysen, D., Raes, J., Leroy, B. P, Lucassen, A., Yates, J. R. W., Clayton-Smith, J., Ilyina, H., Sklower Brooks, S., Christin-Maitre, S., Fellous, M., Fryns, J. P., Kim, J. R., and 11 others.
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<strong>Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.</strong>
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Am. J. Hum. Genet. 77: 205-218, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15962237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15962237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15962237" 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/10.1086/432083" target="_blank">Full Text</a>]
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<a id="Beysen2004" class="mim-anchor"></a>
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Beysen, D., Vandesompele, J., Messiaen, L., De Paepe, A., De Baere, E.
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<strong>The human FOXL2 mutation database.</strong>
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Hum. Mutat. 24: 189-193, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15300845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15300845</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15300845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20079" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Boccone1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Boccone, L., Meloni, A., Falchi, A. M., Usai, V., Cao, A.
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<strong>Blepharophimosis, ptosis, epicanthus inversus syndrome, a new case associated with de novo balanced autosomal translocation [46,XY,t(3;7)(q23;q32)].</strong>
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Am. J. Med. Genet. 51: 258-259, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8074155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8074155</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8074155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320510317" target="_blank">Full Text</a>]
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<a id="Cha2003" class="mim-anchor"></a>
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<div class="">
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Cha, S. C., Jang, Y. S., Lee, J. H., Kim, H. K., Kim, S. C., Kim, S., Baek, S.-H., Jung, W. S., Kim, J.-R.
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<strong>Mutational analysis of forkhead transcriptional factor 2 (FOXL2) in Korean patients with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14986827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14986827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14986827" 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/10.1046/j.1399-0004.2003.00162.x" target="_blank">Full Text</a>]
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<a id="Cocquet2002" class="mim-anchor"></a>
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Cocquet, J., Pailhoux, E., Jaubert, F., Servel, N., Xia, X., Pannetier, M., De Baere, E., Messiaen, L., Cotinot, C., Fellous, M., Veitia, R. A.
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<strong>Evolution and expression of FOXL2. (Letter)</strong>
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J. Med. Genet. 39: 916-922, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.39.12.916" target="_blank">Full Text</a>]
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<a id="Crisponi2001" class="mim-anchor"></a>
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<div class="">
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Crisponi, L., Deiana, M., Loi, A., Chiappe, F., Uda, M., Amati, P., Bisceglia, L., Zelante, L., Nagaraja, R., Porcu, S., Ristaldi, M. S., Marzella, R., and 10 others.
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<strong>The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.</strong>
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Nature Genet. 27: 159-166, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175783</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175783" 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/10.1038/84781" target="_blank">Full Text</a>]
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Crisponi, L., Uda, M., Deiana, M., Loi, A., Nagaraja, R., Chiappe, F., Schlessinger, D., Cao, A., Pilia, G.
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<strong>FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.</strong>
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Genomics 83: 757-764, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15081106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15081106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15081106" 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.ygeno.2003.11.010" target="_blank">Full Text</a>]
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<a id="De Baere2003" class="mim-anchor"></a>
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De Baere, E., Beysen, D., Oley, C., Lorenz, B., Cocquet, J., De Sutter, P., Devriendt, K., Dixon, M., Fellous, M., Fryns, J.-P., Garza, A., Jonsrud, C., and 9 others.
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<strong>FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.</strong>
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Am. J. Hum. Genet. 72: 478-487, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12529855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12529855</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529855" 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/10.1086/346118" target="_blank">Full Text</a>]
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<a id="De Baere2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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De Baere, E., Dixon, M. J., Small, K. W., Jabs, E. W., Leroy, B. P., Devriendt, K., Gillerot, Y., Mortier, G., Meire, F., Van Maldergem, L., Courtens, W., Hjalgrim, H., and 15 others.
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<strong>Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype-phenotype correlation.</strong>
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Hum. Molec. Genet. 10: 1591-1600, 2001.
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[<a href="https://doi.org/10.1093/hmg/10.15.1591" target="_blank">Full Text</a>]
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<a id="De Baere2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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De Baere, E., Lemercier, B., Christin-Maitre, S., Durval, D., Messiaen, L., Fellous, M., Veitia, R.
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<strong>FOXL2 mutation screening in a large panel of POF patients and XX males.</strong>
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J. Med. Genet. 39: e43 only, 2002. Note: Electronic Article.
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[<a href="https://doi.org/10.1136/jmg.39.8.e43" target="_blank">Full Text</a>]
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Dipietromaria, A., Benayoun, B. A., Todeschini, A.-L., Rivals, I., Bazin, C., Veitia, R. A.
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<strong>Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems.</strong>
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Hum. Molec. Genet. 18: 3324-3333, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515849</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515849" 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/ddp273" target="_blank">Full Text</a>]
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Dollfus, H., Stoetzel, C., Riehm, S., Lahlou Boukoffa, W., Bediard Boulaneb, F., Quillet, R., Abu-Eid, M., Speeg-Schatz, C., Francfort, J. J., Flament, J., Veillon, F., Perrin-Schmitt, F.
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<strong>Sporadic and familial blepharophimosis-ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.</strong>
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Clin. Genet. 63: 117-120, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12630957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12630957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12630957" 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/10.1034/j.1399-0004.2003.00011.x" target="_blank">Full Text</a>]
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<a id="Fokstuen2003" class="mim-anchor"></a>
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Fokstuen, S., Antonarakis, S. E., Blouin, J.-L.
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<strong>FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients.</strong>
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Am. J. Med. Genet. 117A: 143-146, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12567411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12567411</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12567411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10024" target="_blank">Full Text</a>]
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Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N.
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<strong>Identification of novel mutations in FOXL2 associated with premature ovarian failure.</strong>
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Molec. Hum. Reprod. 8: 729-733, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12149404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12149404</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12149404" 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/molehr/8.8.729" target="_blank">Full Text</a>]
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<strong>Unified nomenclature for the winged helix/forkhead transcription factors.</strong>
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<strong>Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian blepharophimosis ptosis epicanthus inversus syndrome (BPES) patients.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21325395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21325395</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21325395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/bjo.2009.177972" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.065086" target="_blank">Full Text</a>]
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<a id="Lee2005" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/j.bbrc.2005.08.184" target="_blank">Full Text</a>]
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<a id="Moumne2008" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1093/hmg/ddm373" target="_blank">Full Text</a>]
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<a id="Moumne2005" class="mim-anchor"></a>
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<strong>Deletions in the polyalanine-containing transcription factor FOXL2 lead to intranuclear aggregation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16219626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16219626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16219626" 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/ddi383" target="_blank">Full Text</a>]
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<a id="Nallathambi2007" class="mim-anchor"></a>
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<strong>A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.</strong>
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[<a href="https://doi.org/10.1007/s00439-006-0276-0" target="_blank">Full Text</a>]
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<a id="Ottolenghi2005" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1093/hmg/ddi210" target="_blank">Full Text</a>]
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<a id="Ottolenghi2007" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17728319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17728319</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17728319" 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/ddm235" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng769" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175772</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175772" 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/10.1038/84735" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Ramirez-Castro2002" class="mim-anchor"></a>
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Ramirez-Castro, J. L., Pineda-Trujillo, N., Valencia, A. V., Muneton, C. M., Botero, O., Trujillo, O., Vasquez, G., Mora, B. E., Durango, N., Bedoya, G., Ruiz-Linares, A.
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<strong>Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.</strong>
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Am. J. Med. Genet. 113: 47-51, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12400065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12400065</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12400065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.10741" target="_blank">Full Text</a>]
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<a id="Shah2009" class="mim-anchor"></a>
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Shah, S. P., Kobel, M., Senz, J., Morin, R. D., Clark, B. A., Wiegand, K. C., Leung, G., Zayed, A., Mehl, E., Kalloger, S. E., Sun, M., Giuliany, R., and 29 others.
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<strong>Mutation of FOXL2 in granulosa-cell tumors of the ovary.</strong>
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New Eng. J. Med. 360: 2719-2729, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19516027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19516027</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19516027" 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/10.1056/NEJMoa0902542" target="_blank">Full Text</a>]
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<a id="Shi2014" class="mim-anchor"></a>
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Shi, F., Ding, S., Zhao, S., Han, M., Zhuang, Y., Xu, T., Wu, X.
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<strong>A piggyBac insertion disrupts Foxl2 expression that mimics BPES syndrome in mice.</strong>
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Hum. Molec. Genet. 23: 3792-3800, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24565867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24565867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24565867" 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/ddu092" target="_blank">Full Text</a>]
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<a id="Uda2004" class="mim-anchor"></a>
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Uda, M., Ottolenghi, C., Crisponi, L., Garcia, J. E., Deiana, M., Kimber, W., Forabosco, A., Cao, A., Schlessinger, D., Pilia, G.
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<strong>Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.</strong>
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Hum. Molec. Genet. 13: 1171-1181, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15056605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15056605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15056605" 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/ddh124" target="_blank">Full Text</a>]
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<a id="Udar2003" class="mim-anchor"></a>
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Udar, N., Yellore, V., Chalukya, M., Yelchits, S., Silva-Garcia, R., BPES Consortium, Small, K.
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<strong>Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients.</strong>
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Hum. Mutat. 22: 222-228, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12938087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12938087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12938087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10251" target="_blank">Full Text</a>]
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<a id="Uhlenhaut2009" class="mim-anchor"></a>
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Uhlenhaut, N. H., Jakob, S., Anlag, K., Eisenberger, T., Sekido, R., Kress, J., Treier, A.-C., Klugmann, C., Klasen, C., Holter, N. I., Riethmacher, D., Schutz, G., Cooney, A. J., Lovell-Badge, R., Treier, M.
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<strong>Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.</strong>
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Cell 139: 1130-1142, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20005806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20005806</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20005806" 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.cell.2009.11.021" target="_blank">Full Text</a>]
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Vaiman, D., Schibler, L., Oustry-Vaiman, A., Pailhoux, E., Goldammer, T., Stevanovic, M., Furet, J.-P., Schwerin, M., Cotinot, C., Fellous, M., Cribiu, E. P.
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<strong>High-resolution human/goat comparative map of the goat polled/intersex syndrome (PIS): the human homologue is contained in a human YAC from HSA3q23.</strong>
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Genomics 56: 31-39, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10036183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10036183</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10036183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5691" target="_blank">Full Text</a>]
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Vincent, A. L., Watkins, W. J., Sloan, B. H., Shelling, A. N.
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<strong>Blepharophimosis and bilateral Duane syndrome associated with a FOXL2 mutation.</strong>
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Clin. Genet. 68: 520-523, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283882</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283882" 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/10.1111/j.1399-0004.2005.00527.x" target="_blank">Full Text</a>]
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Yamada, T., Hayasaka, S., Matsumoto, M., Budu, Esa, T., Hayasaka, Y., Endo, M.
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<strong>Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong>
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J. Hum. Genet. 46: 733-736, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11776388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11776388</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11776388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100380170009" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 11/17/2014
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 4/17/2012<br>Matthew B. Gross - updated : 3/26/2012<br>Patricia A. Hartz - updated : 3/23/2012<br>Marla J. F. O'Neill - updated : 11/15/2011<br>Jane Kelly - updated : 8/15/2011<br>Marla J. F. O'Neill - updated : 9/24/2010<br>George E. Tiller - updated : 7/7/2010<br>Patricia A. Hartz - updated : 1/29/2010<br>Joanna S. Amberger - updated : 1/25/2010<br>Patricia A. Hartz - updated : 11/4/2009<br>Marla J. F. O'Neill - updated : 10/12/2009<br>George E. Tiller - updated : 8/10/2009<br>Marla J. F. O'Neill - updated : 7/14/2009<br>George E. Tiller - updated : 4/23/2009<br>George E. Tiller - updated : 11/18/2008<br>Cassandra L. Kniffin - updated : 5/11/2007<br>Marla J. F. O'Neill - updated : 10/25/2006<br>George E. Tiller - updated : 9/6/2006<br>Marla J. F. O'Neill - updated : 8/30/2005<br>Victor A. McKusick - updated : 10/20/2004<br>Victor A. McKusick - updated : 9/30/2004<br>Deborah L. Stone - updated : 7/23/2004<br>Patricia A. Hartz - updated : 5/13/2004<br>Victor A. McKusick - updated : 1/12/2004<br>Victor A. McKusick - updated : 10/14/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 4/22/2003<br>Victor A. McKusick - updated : 2/27/2003<br>Victor A. McKusick - updated : 11/7/2002<br>Victor A. McKusick - updated : 3/6/2002<br>George E. Tiller - updated : 12/18/2001<br>Victor A. McKusick - updated : 12/3/2001
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 1/26/2001
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alopez : 02/21/2025
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carol : 11/08/2019<br>carol : 06/28/2019<br>carol : 06/29/2018<br>carol : 03/28/2018<br>carol : 04/18/2017<br>carol : 04/17/2017<br>mgross : 11/19/2014<br>mcolton : 11/17/2014<br>mgross : 4/17/2012<br>terry : 4/17/2012<br>mgross : 3/26/2012<br>mgross : 3/26/2012<br>terry : 3/23/2012<br>carol : 11/15/2011<br>terry : 11/15/2011<br>carol : 8/17/2011<br>terry : 8/15/2011<br>wwang : 9/24/2010<br>terry : 9/24/2010<br>wwang : 7/21/2010<br>terry : 7/7/2010<br>mgross : 1/29/2010<br>terry : 1/29/2010<br>mgross : 1/25/2010<br>joanna : 1/25/2010<br>mgross : 11/12/2009<br>terry : 11/4/2009<br>wwang : 10/29/2009<br>terry : 10/12/2009<br>wwang : 8/20/2009<br>terry : 8/10/2009<br>carol : 7/15/2009<br>terry : 7/14/2009<br>wwang : 5/13/2009<br>terry : 4/23/2009<br>wwang : 12/9/2008<br>wwang : 11/18/2008<br>terry : 9/10/2008<br>wwang : 7/28/2008<br>wwang : 5/14/2007<br>ckniffin : 5/11/2007<br>wwang : 10/26/2006<br>terry : 10/25/2006<br>alopez : 9/6/2006<br>wwang : 8/30/2005<br>terry : 8/3/2005<br>alopez : 11/2/2004<br>alopez : 10/27/2004<br>tkritzer : 10/21/2004<br>terry : 10/20/2004<br>tkritzer : 10/5/2004<br>terry : 9/30/2004<br>tkritzer : 7/30/2004<br>terry : 7/23/2004<br>mgross : 5/19/2004<br>mgross : 5/19/2004<br>terry : 5/13/2004<br>carol : 1/20/2004<br>terry : 1/12/2004<br>cwells : 11/5/2003<br>alopez : 10/14/2003<br>tkritzer : 7/15/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>tkritzer : 4/29/2003<br>terry : 4/22/2003<br>carol : 3/4/2003<br>tkritzer : 3/3/2003<br>terry : 2/27/2003<br>tkritzer : 11/18/2002<br>tkritzer : 11/13/2002<br>terry : 11/7/2002<br>cwells : 3/14/2002<br>cwells : 3/12/2002<br>terry : 3/6/2002<br>cwells : 12/28/2001<br>cwells : 12/18/2001<br>alopez : 12/3/2001<br>terry : 12/3/2001<br>alopez : 3/14/2001<br>joanna : 2/20/2001<br>mcapotos : 2/12/2001<br>alopez : 2/8/2001<br>alopez : 2/1/2001<br>alopez : 1/26/2001
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<strong>*</strong> 605597
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<h3>
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FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2
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PITUITARY FORKHEAD FACTOR, MOUSE, HOMOLOG OF; PFRK
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FOXL2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 715391004;
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</span>
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</p>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:138,944,224-138,947,137 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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3q22.3
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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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Blepharophimosis, epicanthus inversus, and ptosis, type 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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110100
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Blepharophimosis, epicanthus inversus, and ptosis, type 2
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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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110100
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Premature ovarian failure 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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608996
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Transcription factors belonging to the evolutionarily conserved forkhead box (FOX) superfamily contain a DNA-binding motif known as the forkhead box or winged-helix domain. The forkhead box domain is about 100 amino acids long and folds into a structure containing 3 N-terminal alpha helices, 3 beta strands, and 2 loop regions near the C-terminal end of the domain. In contrast with the highly conserved forkhead box domain, FOX proteins are highly divergent in other parts of their sequences. FOX proteins vary widely in their expression patterns, regulation, and physiologic functions, with roles in eye organogenesis, language acquisition, stress response, aging regulation, and tumor suppression. FOXL2 plays a crucial role in ovarian development and female fertility (summary by Benayoun et al., 2008). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Crisponi et al. (2001) positionally cloned a novel putative winged helix/forkhead transcription factor gene, FOXL2, in the blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; 110100) critical region on chromosome 3q23. Consistent with an involvement in BPES, FOXL2 was selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appeared predominantly in the ovary. </p><p>Cocquet et al. (2002) found that the FOXL2 coding region is highly conserved in human, goat, mouse, and pufferfish. They showed that the number of alanine residues is strictly conserved among the mammals studied, suggesting the existence of strong functional or structural constraints. They provided immunohistochemical evidence indicating that FOXL2 is a nuclear protein specifically expressed in eyelids and in fetal and adult ovarian follicular cells. It does not undergo any major posttranslational maturation. They pointed out that FOXL2 is the earliest known marker of ovarian differentiation in mammals and may play a role in ovarian somatic cell differentiation and in further follicle development and/or maintenance. </p><p>Udar et al. (2003) sequenced the mouse homolog for the FOXL2 gene and identified the Fugu rubripes (pufferfish) ortholog by screening the Joint Genome Institute database (Aparicio et al., 2002) with the mouse genomic sequence. By alignment of the human, mouse, and pufferfish sequences, they found an almost complete conservation of the forkhead domain in the 3 species. There is 95% and 61% conservation at the protein level between human-mouse and human-pufferfish, respectively. The polyalanine and polyproline tracts within the gene are absent in pufferfish. </p><p>Beysen et al. (2008) stated that the 376-amino acid FOXL2 protein has a DNA-binding forkhead domain (FHD) of about 110 amino acids and a polyalanine tract of 14 residues. </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>Crisponi et al. (2004) determined that mouse and human FOXL2 are single-exon genes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Crisponi et al. (2001) mapped the FOXL2 gene to chromosome 3q23. </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>More than 99% of ovarian germ cells undergo atresia. Lee et al. (2005) found that overexpression of human FOXL2 caused apoptosis in Chinese hamster ovary cells and in primed rat granulosa cells in a dose-dependent manner. Apoptosis was prevented by cotransfection of a baculoviral caspase inhibitor. Yeast 2-hybrid analysis revealed that FOXL2 interacted with the C-terminal domain of mouse Dp103 (DDX20; 606168), an ATP-dependent RNA helicase. The region of Dp103 that interacted with FOXL2 lacks the helicase domain, but it also interacts with SF1 (NR5A1; 184757), a nuclear factor involved in sex determination. Dp103 had no effect on cell viability alone, but cotransfection studies showed that Dp103 enhanced the apoptotic effect of FOXL2. </p><p>By PCR selection using a library of double-stranded DNA fragments and nuclear extracts of a mouse granulosa cell line, Benayoun et al. (2008) identified a Foxl2 response element (FLRE) that differed significantly from other FOX protein-binding sites. The common 7-bp FLRE was 5-prime-GT(C/G)AAGG-3-prime, or its reverse complement. By transfecting mouse and human granulosa-like cells with artificial promoter reporters, Benayoun et al. (2008) found that 4 tandem copies of FLRE resulted in higher reporter activity than 2, and that replacement of Gs with Ts in the FLRE core sequence resulted in an FLRE with lower FOXL2 affinity and weaker reporter activity. In addition, poly(A) expansion of FOXL2, notably expansion to 24 alanines (FOXL2-ala24), resulted in lower reporter activity when the reporter had fewer FLREs or when the FLRE had lower FOXL2 affinity. FOXL2-ala24 functioned in a dominant-negative fashion when coexpressed with wildtype FOXL2, but only with a reporter of low FOXL2 affinity. Benayoun et al. (2008) concluded that the impact of poly(A) expansion on expression of FOXL2-dependent genes depends on both the number and specific sequences of FLREs in FOXL2-responsive promoters. </p><p>Benayoun et al. (2009) showed that cell stress upregulated FOXL2 expression in an ovarian granulosa cell model. The response of FOXL2 to stress correlated with a dramatic remodeling of its posttranslational modification profile. Upon oxidative stress, there was increased recruitment of FOXL2 to several stress-response promoters, notably mitochondrial manganese superoxide dismutase, MnSOD (SOD2; 147460). FOXL2 activity was repressed by the SIRT1 (604479) deacetylase. SIRT1 transcription was, in turn, directly upregulated by FOXL2, which closed a negative-feedback loop. Treatment with the sirtuin inhibitor nicotinamide increased FOXL2 transcription. Eleven disease-causing mutations in the ORF of FOXL2 induced aberrant regulation of FOXL2 and/or the FOXL2 stress-response target gene MnSOD. Benayoun et al. (2009) concluded that FOXL2 is an actor of the stress response. </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>Blepharophimosis, Ptosis, and Epicanthus Inversus, Types I and II</em></strong></p><p>
|
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There are 2 forms of the blepharophimosis/ptosis/epicanthus inversus syndrome (BPES; 110100). In type I, eyelid abnormalities are associated with ovarian failure. In type II, only the eyelid defects are found. Crisponi et al. (2001) identified mutations in the FOXL2 gene that produced truncated proteins in type I families and larger proteins in type II families. Because of the variable phenotypes produced by mutations in forkhead transcription factor genes, Crisponi et al. (2001) proposed that some mutations in the FOXL2 gene may be associated with other phenotypes, including nonsyndromic premature ovarian failure (POF; see 608996). FOXL2 was the third forkhead gene found to be involved in the pathogenesis of inherited developmental human disorders. A single-exon gene, FOXE1 (602617), is mutated in cases of thyroid agenesis, and FOXC1 (601090) is mutated in eye defects associated with congenital glaucoma. </p><p>In a study in Korean patients, Cha et al. (2003) identified FOXL2 mutations in 5 of 9 BPES families and 3 of 7 sporadic cases. No causal mutation was found in the other BPES families or sporadic cases, suggesting that the genetic defect in some BPES patients may reside in the noncoding region of the FOXL2 gene or in other genes. </p><p>Vincent et al. (2005) reported an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see 126800), in whom they identified a heterozygous duplication of 10 alanine residues in the FOXL2 gene (605597.0002). </p><p>In an Indian cohort comprising 6 familial and 2 sporadic cases of BPES type I or type II, Kaur et al. (2011) identified 6 heterozygous mutations in the FOXL2 gene, 3 of which were novel (see, e.g., 605597.0020). In 1 family, an affected female also had polycystic ovarian disease. Kaur et al. (2011) noted that mutations in the region downstream of the forkhead domain were predominantly responsible for BPES among Indian patients. </p><p><strong><em>Premature Ovarian Failure 3</em></strong></p><p>
|
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Harris et al. (2002) detected heterozygous FOXL2 mutations in 2 patients with isolated POF (POF3; 608996). One mutation removed 10 of the 14 alanines in the polyalanine tract downstream of the winged helix/forkhead domain (605597.0016). The other was a single-nucleotide substitution predicted to result in a tyr258-to-asn amino acid change (Y258N; 605597.0017). </p><p>In a 27-year-old Tunisian patient with nonsyndromic premature ovarian failure, Laissue et al. (2009) identified a heterozygous mutation in the FOXL2 gene (G187D; 605597.0019). Although the transactivation capacity of FOXL2-G187D was significantly lower than that of wildtype FOXL2, the mutant was able to strongly activate a reporter construct driven by the OSR2 (611297) promoter, believed to be a crucial target of FOXL2 in the craniofacial region. Laissue et al. (2009) noted that this is compatible with the absence of BPES in this patient. </p><p><strong><em>Ovarian Granulosa-Cell Tumors</em></strong></p><p>
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Shah et al. (2009) analyzed 4 adult-type ovarian granulosa-cell tumor (GCT) specimens for GCT-specific mutations and identified a somatic point mutation, 402C-G (C134W), in the FOXL2 gene in all 4 specimens. The C134W mutation was present in 86 (97%) of 89 additional adult-type GCTs, in 3 (21%) of 14 thecomas, and in 1 (10%) of 10 juvenile-type GCTs. The mutation was absent in 49 sex cord/stromal tumors of other types and in 329 unrelated ovarian or breast tumors. Shah et al. (2009) concluded that mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs. </p><p><strong><em>FOXL2 Mutation Database</em></strong></p><p>
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Beysen et al. (2004) described a locus-specific human FOXL2 mutation database available on the Internet. The database contained approximately 135 intragenic mutations and variants of FOXL2, but did not include variants residing outside the coding region of FOXL2 or molecular cytogenetic rearrangements of the FOXL2 locus. Beysen et al. (2004) stated that at least 1 mutation in the FOXL2 gene with a putative pathogenic effect had been found in patients affected with isolated primary ovarian failure (Harris et al., 2002). </p><p><strong><em>Pathogenic Effects of FOXL2 Mutations</em></strong></p><p>
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Moumne et al. (2005) showed that premature stop codons in the FOXL2 gene (e.g., 605597.0008) may lead to the production of N-terminally truncated proteins by reinitiation of translation downstream of the stop codon. Truncated proteins strongly aggregated in the nucleus, partially localized in the cytoplasm, and retained a fraction of the wildtype protein. A complete deletion of the polyalanine tract of FOXL2 induced significant intranuclear aggregation. </p><p>Moumne et al. (2008) noted that polyalanine expansions of +10 residues (i.e., 24 alanines) in FOXL2 have been identified in approximately 30% of BPES patients and are mainly responsible for BPES type II. By transfecting COS-7 and KGN cells with a series of FOXL2 polyalanine variants, Moumne et al. (2008) found that the wildtype allele with 14 alanines was expressed exclusively in the nucleus. Cytoplasmic staining became statistically significant for FOXL2 containing 19 alanines, and it reached 100% for 37 alanines. FOXL2 proteins with 24 alanines or more showed aggregation in both nuclear and cytoplasmic compartments. FRAP analysis showed that wildtype FOXL2 was highly mobile within the nuclear compartment, while FOXL2 with 17 alanines showed reduced mobility, and FOXL2 with 19 alanines was virtually immobile. Reporter gene assays using the promoter regions of several FOXL2 target genes showed that alanine expansion had variable effects on promoter activity. Moumne et al. (2008) suggested that promoters with more FOXL2-binding sites or higher FOXL2 affinity would be less sensitive than other promoters to reduced FOXL2 availability due to protein aggregation or mislocalization. </p><p>By expression in COS-7 and KGN cells, Beysen et al. (2008) examined the consequences of 16 missense mutations within the DNA-binding FHD of FOXL2 and another mutation outside the FHD. The mutations had variable effects on subcellular localization, aggregation, and transactivation of a reporter gene. </p><p>Dipietromaria et al. (2009) dissected the molecular and functional effects of 10 FOXL2 mutants, known to induce BPES with or without premature ovarian failure (POF). There was a correlation between the transcriptional activity of FOXL2 variants on 2 different reporter promoter assays (4XFLRE-luc and SIRT1-luc) and the type of BPES. Application of this functional framework to 18 BPES missense mutations allowed classification as type I or II mutation based on transactivation abilities. They also found a loose correlation between intranuclear aggregation and cytoplasmic mislocalization of mutant FOXL2 and the type of BPES. Dipietromaria et al. (2009) suggested that a FOXL2 mutant completely lacking activity on the 2 reporter assays used in this study is likely to lead to BPES with POF. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>De Baere et al. (2001) identified FOXL2 mutations in 21 of 34 patients with BPES types I and II. A genotype-phenotype correlation was evident, wherein mutations predicted to result in a truncated protein either lacking or containing the forkhead domain led to BPES type I. In contrast, duplications within or downstream of the forkhead domain and a frameshift downstream of them, all predicted to result in an extended protein, caused BPES type II. In 30 unrelated patients with isolated premature ovarian failure, no causal mutations were identified in FOXL2. The initial association of BPES type I and mutations in the FOXL2 gene raised the question of whether mutations in FOXL2 could lead to isolated POF (Prueitt and Zinn, 2001). </p><p>De Baere et al. (2003) described 21 FOXL2 mutations, 16 of which were novel, and stated that 53 mutations in the FOXL2 had been reported. Two mutation hotspots were identified: 30% of FOXL2 mutations led to polyalanine expansions, and 13% were novel out-of-frame duplications. They demonstrated intra- and interfamilial phenotypic variability, with both BPES types caused by the same mutation (see 605597.0006 and 605597.0009). They found exceptions to their previously constructed genotype-phenotype correlation, which required revision. They assumed that for predicted proteins with a truncation before the polyalanine tract, the risk for development of POF was high. For mutations leading to a truncated or extended protein containing an intact forkhead and polyalanine tract, no predictions were possible, because some of these mutations led to both types of BPES, even within the same family. Polyalanine expansions may lead to BPES type II (see 605597.0010). For missense mutations, no correlations could be made. Microdeletions were associated with mental retardation. </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>Cytogenetics</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>Boccone et al. (1994) described a de novo, apparently balanced, reciprocal translocation between the long arms of chromosomes 3 and 7 in a 2-year-old male with BPES; the breakpoints were 3q23 and 7q32. Crisponi et al. (2004) found that the chromosome 3 breakpoint in this patient was located about 170 kb upstream of the FOXL2 gene, within exon 6 of the MRPS22 gene (605810), which is transcribed in the opposite orientation. They identified regions within introns 6, 11, and 12 of the MRPS22 gene that may regulate FOXL2 expression, including a winged-helix transcription factor-binding site in intron 11. Crisponi et al. (2004) reviewed other examples of distant defects that alter gene function, including a translocation 120 kb from the FOXC2 (602402) gene that causes lymphedema-distichiasis syndrome (153400) and a translocation more than 150 kb from the PAX6 gene (607108) that causes aniridia (106210). They suggested several models for long-range regulation of FOXL2 gene expression, including higher order genome structures that bring distant regulatory sequences within proximity of gene transcription start sites. </p><p>In 2 sporadic patients and 2 families with BPES, Beysen et al. (2005) identified 4 overlapping extragenic microdeletions, ranging from 126 kb to 1.9 Mb in size, 230 kb upstream of the FOXL2 gene. The shortest region of deletion overlap contains several conserved nongenic sequences harboring putative transcription factor-binding sites and representing potential long-range cis-regulatory elements. In another family with BPES, Beysen et al. (2005) identified an approximately 188-kb microdeletion downstream of the FOXL2 gene. The father of the 2 affected half-sisters was unaffected, suggestive of germinal mosaicism; quantitative analysis using 3 SNPs located in the deletion showed that about 10% of paternal germ cells and 5% of somatic peripheral blood lymphocytes carried the mutation. </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>Crisponi et al. (2001) pointed out that polled/intersex syndrome (PIS) in the goat has been suggested to be an animal model of human BPES (Vaiman et al., 1999). It maps to 1q31 in the goat, a region homologous to human 3q23. Thus, the authors hypothesized that the goat FOXL2 gene may be the site of the mutation causing PIS. </p><p>Pailhoux et al. (2001) found by a positional cloning approach that the mutation underlying PIS in the goat is the deletion of a critical 11.7-kb DNA element containing mainly repetitive sequences. This deletion was shown to affect the transcription of at least 2 genes: PISRT1, encoding a 1.5-kb mRNA devoid of open reading frame, and FOXL2. These 2 genes are located 20 and 200 kb telomeric from the deletion, respectively. </p><p>Uda et al. (2004) reported that mice lacking Foxl2 recapitulated relevant features of human BPES: males and females were small and showed distinctive craniofacial morphology with absent upper eyelids. Furthermore, in mice as in humans, sterility was confined to females: all major somatic cell lineages failed to develop around growing oocytes from the time of primordial follicle formation. </p><p>Ottolenghi et al. (2005) found that mouse XX gonads lacking Foxl2 formed meiotic prophase oocytes, but then activated the genetic program for somatic testis determination. Pivotal Foxl2 action repressed the male gene pathway at several stages of female gonadal differentiation. The authors proposed a continued involvement of sex-determining genes in maintaining ovarian function throughout female reproductive life. </p><p>Ottolenghi et al. (2007) observed formation of testis-like tubules and spermatogonia in the ovaries of Wnt4/Foxl2 double-knockout XX mice, demonstrating that female sex-determining genes, the putative 'ovary organizer,' are required to suppress an alternative male fate in the ovary and act as a female equivalent of SRY (480000). Forced expression of Foxl2 impaired testis tubule differentiation in XY transgenic mice, and germ cell-depleted XX mice lacking Foxl2 and harboring a Kit (164920) mutation underwent partial female-to-male sex reversal. Ottolenghi et al. (2007) stated that the results were all consistent with an anti-testis role for FOXL2. </p><p>Uhlenhaut et al. (2009) found that Foxl2 was required to prevent transdifferentiation of an adult mouse ovary to a testis. Foxl2 repressed testis differentiation in vivo mainly through repression of the Sox9 (608160) cis-regulatory sequence TESCO. Foxl2 and estrogen receptor (ESR1; 133430) cooperated in Sox9 repression in vivo, thus providing a mechanism by which loss of estrogen signaling could lead to gonadal sex reversal. </p><p>Using piggyBac (PB) insertional mutagenesis, Shi et al. (2014) created a line of mice with a modest yet significant reduction in Foxl2 expression and a BPES-like phenotype. Homozygous PB/PB mice began to lose weight approximately 2 weeks after birth, and most died within the first month of life. At 3 weeks of age, they showed significant overgrowth of mandibular incisors with malocclusion, and some showed palpebral anomalies and periocular hair loss. Surviving female PB/PB mice were subfertile, with smaller than normal ovaries and uteri. Shi et al. (2014) mapped the PB insertion site to a region approximately 160 kb upstream of the Foxl2 transcription start site and approximately 10 kb upstream of an element, ECF1, that showed a high degree of conservation among goat, mouse, and human. ECF1 functioned as an enhancer in reporter gene assays and interacted directly with the Foxl2 promoter in chromosome conformation capture assays. Shi et al. (2014) noted that BPES patients with balanced translocations and chromosome breakpoints 130, 160, or 171 kb upstream of FOXL2 have been reported. The authors hypothesized that these translocations may isolate transcription regulatory elements, including the human ECF1 ortholog, leading to FOXL2 misregulation. </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>Nomenclature</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>See Kaestner et al. (2000) for a unified nomenclature for winged helix/forkhead transcription factors. </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>20 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 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</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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FOXL2, GLN219TER
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<br />
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SNP: rs104893741,
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ClinVar: RCV000005126, RCV000192033, RCV003555920, RCV004795376
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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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<div class="mim-changed mim-change"><p>In a family with type I BPES (110100), Crisponi et al. (2001) found that affected members had a C-to-T transition at position c.892, resulting in a codon that predicted a truncated protein (gln219 to ter). </p></div>
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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 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</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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BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II WITH DUANE RETRACTION SYNDROME, 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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FOXL2, 30-BP DUP, NT909
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<br />
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SNP: rs387906321,
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gnomAD: rs387906321,
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ClinVar: RCV000005127, RCV000005128, RCV000408801, RCV002512795
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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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<div class="mim-changed mim-change"><p>In affected members of 2 families with BPES type II (110100), and in a sporadic male BPES patient, Crisponi et al. (2001) identified a 30-bp duplication at position 909 to 938 (c.909_938dup). Amino acids 224 to 234 were duplicated. In the 2 families with multiple cases, affected females transmitted the trait to the next generation. </p></div>
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|
<p>Ramirez-Castro et al. (2002) identified this mutation in affected members of 2 families with BPES type II from a historically isolated population in northwest Colombia. The genotype/phenotype correlation in the families was consistent with a proposal that BPES type I is caused by truncating mutations leading to haploinsufficiency, while BPES type II is caused by mutations generating elongated protein products (see also 605597.0008). This duplication has also been described as recurrent in unrelated familial and sporadic BPES cases in Europe; its recurrence may be related to the secondary structure of the particular DNA region. </p>
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<p>In both a family and sporadic case of BPES type II from Algeria, Dollfus et al. (2003) identified this mutation. </p>
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|
<p>In an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see 126800), Vincent et al. (2005) identified heterozygosity for a 30-bp duplication, which they designated 672_701dup30 based on numbering from the ATG start codon, resulting in a duplication of 10 alanine residues at codon 224 in the FOXL2 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FOXL2, 2-BP DEL, 290CA
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<br />
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SNP: rs863225450,
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ClinVar: RCV000005129
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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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|
<div class="mim-changed mim-change"><p>In a family with BPES type I (110100), De Baere et al. (2001) found that affected members had a CA dinucleotide deletion from position 290 to 291 (c.290_291delCA), resulting in a frameshift generating 76 novel amino acids and terminating prematurely at codon 94. The entire forkhead domain was obliterated. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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FOXL2, 8-BP DUP, NT1149
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<br />
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SNP: rs863225451,
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|
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ClinVar: RCV000005130
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with BPES type I (110100), De Baere et al. (2001) found that affected members had an 8-bp duplication at position 1149 to 1156, resulting in a frameshift generating 50 novel amino acids and terminating prematurely at codon 358. Neither the forkhead domain nor the polyalanine tract were disrupted. </p>
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</span>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 15-BP DUP, NT415
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|
|
|
|
|
<br />
|
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|
|
SNP: rs863225452,
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|
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|
|
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|
|
ClinVar: RCV000005131, RCV000785831
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with BPES type II (110100), De Baere et al. (2001) found that affected members had a 15-bp duplication at position 415 to 429, resulting in duplication of amino acids 60 to 64 within the forkhead domain. </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>.0006 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 1-BP INS, 1041C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs797044528,
|
|
|
|
|
|
gnomAD: rs797044528,
|
|
|
|
|
|
ClinVar: RCV000005132, RCV000005133, RCV000192036, RCV000727228, RCV004619186, RCV004795377
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families with BPES II (110100), De Baere et al. (2001) found that affected members had a 1-bp cytosine insertion following position 1041, resulting in 264 novel amino acids beginning at codon 268 and extending the protein from 376 amino acids to 532 amino acids. </p><p>De Baere et al. (2003) found this mutation in a family with BPES I. They stated that this was the first mutation shown to lead to both BPES types in different families (interfamilial phenotypic variability). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 17-BP DEL, NT1092
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs797044532,
|
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|
|
|
|
|
ClinVar: RCV000005134, RCV000192041
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese family with BPES type II (110100), Yamada et al. (2001) found a heterozygous 17-bp deletion at nucleotide 1092 in the FOXL2 gene. BPES type II was suspected because the affected woman had 3 sons. Four individuals in 3 sibships in 3 generations were affected. There was 1 instance of male-to-male transmission. </p><p>A 17-bp duplication at nucleotide 1092 was described by Udar et al. (2003) in 3 unrelated pedigrees, indicating that nucleotide 1092 is a hotspot; see 605597.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, GLN53TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs104893737,
|
|
|
|
|
|
|
|
ClinVar: RCV000005135, RCV000760402
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a family from a historically isolated population in northwest Colombia with BPES type I (110100), Ramirez-Castro et al. (2002) demonstrated linkage to chromosome 3q23 and found a novel c.394C-T mutation of the FOXL2 gene which deleted the forkhead DNA binding domain. This mutation resulted in the creation of a stop codon at position 53 (Q53X) of FOXL2. </p></div>
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|
|
|
<p>Moumne et al. (2005) showed that the Q53X mutation could result in production of N-terminally truncated proteins by reinitiation of translation downstream of the stop codon. The Q53X fusion protein was detected by Western blot analysis as a band corresponding to initiation at codon 137 and localized to the nucleus. </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>.0009 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II, INCLUDED
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
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|
|
FOXL2, TYR274TER
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<br />
|
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|
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SNP: rs104893738,
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|
|
|
|
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ClinVar: RCV000005136, RCV000005137, RCV002496265
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|
|
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</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>De Baere et al. (2003) reported a family in which BPES (110100) was related to a c.1059C-G transversion in the FOXL2 gene, predicted to result in a nonsense tyr274-to-ter (Y274X) mutation. The mother was affected by BPES type II and she transmitted the disease to her daughter, who was affected by BPES type I. The latter received ovum donation at age 33 years, resulting in 1 successful pregnancy. De Baere et al. (2003) stated that this was the first reported case in which both types of BPES caused by the same mutation were documented in the same family, indicating intrafamilial phenotypic variability. </p></div>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
FOXL2, 15-BP INS, NT921, ALANINE TRACT EXPANSION
|
|
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|
|
|
<br />
|
|
|
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SNP: rs387906322,
|
|
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|
|
|
|
|
ClinVar: RCV000005138, RCV002490318
|
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|
|
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</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with BPES type II (110100), De Baere et al. (2003) found a novel in-frame 15-bp triplication of nucleotides 921-935 in the FOXL2 gene, leading to a polyalanine expansion of 5 alanine residues, 228-232. They stated that this was the first triplication observed in the polyalanine tract of FOXL2. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
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|
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|
FOXL2, ILE84SER
|
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|
<br />
|
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|
|
SNP: rs28937884,
|
|
|
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|
|
|
|
ClinVar: RCV000005139, RCV003894790
|
|
|
|
|
|
</span>
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|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Dollfus et al. (2003) studied a family originating from Strasbourg, France, that was considered to be one of the largest reported BPES type I (110100) families. The first reported case in this family was born in 1841 from presumed unaffected parents, and thereafter 36 affected individuals were identified over 6 generations. The affected members of the family had typical BPES features. Only males, strikingly and exclusively, transmitted the disease, as affected females were known to be infertile. A 488T-G transversion (genomic sequence numbering) in the FOXL2 gene, resulting in an ile84-to-ser (I84S) mutation, segregated with the disorder in the family. On MRI studies, the superior levator palpebrae could not be seen in 4 patients and appeared to be very thin in a fifth patient, but the other oculomotor muscles appeared to be normal on the MRI images. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
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|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FOXL2, GLN99TER
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<br />
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SNP: rs121908358,
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gnomAD: rs121908358,
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ClinVar: RCV000005140, RCV003231089
|
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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 24-month-old French girl with sporadic BPES type I (110100), Dollfus et al. (2003) identified a 532C-T transition (genomic sequence numbering) in the FOXL2 gene, resulting in a GLN98TER (Q98X) mutation. The mutation resulted in a truncated protein and was not found in her parents or 3 sibs. </p><p>As indicated in the report of Beysen et al. (2008), the amino acid at position 98 in FOXL2 is tryptophan. The correct nomenclature for the mutation reported by Dollfus et al. (2003) is gln99 to ter (Q99X), not GLN98TER. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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FOXL2, GLN196TER
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<br />
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SNP: rs104893739,
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|
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|
|
|
|
|
ClinVar: RCV000005141
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a male with BPES (110100), Udar et al. (2003) found a spontaneous c.823C-T transition in the FOXL2 gene that resulted in a truncation (gln196 to ter; Q196X) of the putative protein downstream of the forkhead domain. The nucleotides and amino acid residues at this position are conserved in human, mouse, and pufferfish. </p></div>
|
|
</span>
|
|
</div>
|
|
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<div>
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|
<br />
|
|
</div>
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|
|
|
</div>
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|
<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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|
<span class="mim-text-font">
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|
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FOXL2, 17-BP DUP, NT1092
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<br />
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|
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SNP: rs797044532,
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|
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|
|
|
|
ClinVar: RCV000005142, RCV000192040, RCV000599160
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 3 affected members of a family with BPES type I (110100), Crisponi et al. (2001) reported a duplication of 17 bp at position 1092-1108 (c.1092_1108dup17), causing a frameshift resulting in a shorter protein. In a mutation search by direct sequencing in 9 affected individuals representing familial or sporadic cases, Udar et al. (2003) found this mutation in 3 unrelated pedigrees. There is a proline tract at this position, and the mutation results in a His291fsTer361 frameshift. A deletion mutation involving the same 17 bases was reported in a Japanese BPES patient by Yamada et al. (2001); see (605597.0007). </p></div>
|
|
</span>
|
|
</div>
|
|
|
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 1-BP INS, 959G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225453,
|
|
|
|
|
|
|
|
ClinVar: RCV000005143
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 32-year-old woman with sporadic BPES type I (110100) and a history of menstrual irregularities and periods of secondary amenorrhea, Fokstuen et al. (2003) identified a heterozygous 1-bp insertion in the FOXL2 gene, c.959insG, resulting in 212 novel amino acids at the carboxyl end of the protein beginning at codon 321 and extending the protein from 376 to 532 amino acids. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 PREMATURE OVARIAN FAILURE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 30-BP DEL, NT898
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000005144, RCV003311650
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 17-year-old Slovenian woman with premature ovarian failure-3 (POF3; 608996), Harris et al. (2002) identified a heterozygous 30-bp deletion (c.898_927del) that removed 10 of the 14 alanines from a polyalanine tract downstream of the winged helix/forkhead domain of the protein (A221_A230del). The patient was identified in a screening of the FOXL2 gene in 70 patients from New Zealand and Slovenia with premature ovarian failure. The patient's mother and sister did not carry the variant; her father was deceased. Harris et al. (2002) stated that this was the first report of a deletion within a polyalanine tract being associated with a disease phenotype, although polyalanine expansions are known to be causative in several conditions; for example, in some families with BPES type II (110100), the polyalanine tract of FOXL2 has been shown to be expanded (605597.0010). </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 PREMATURE OVARIAN FAILURE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, TYR258ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28937885,
|
|
|
|
|
|
gnomAD: rs28937885,
|
|
|
|
|
|
ClinVar: RCV000005145, RCV000987342, RCV005089174
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a woman from New Zealand who underwent premature ovarian failure (POF3; 608996) at the age of 38 years, Harris et al. (2002) identified a heterozygous c.1009T-A transversion in the FOXL2 gene, resulting in a tyr258-to-asn (Y258N) substitution. Her mother also carried the mutation. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE I</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, 15-BP DUP, NT684, ALANINE TRACT EXPANSION
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000005146
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In 3 affected males and 1 affected female of a consanguineous Indian family with BPES type I (110100), Nallathambi et al. (2007) identified a homozygous 15-bp duplication (c.684-698dup15), resulting in an in-frame polyalanine expansion from 14 to 19 residues (Ala19). Several unaffected relatives were heterozygous for the mutation, indicating autosomal recessive inheritance in this family. The affected 30-year-old woman had amenorrhea and impaired fertility, consistent with ovarian dysfunction. Transfection studies in COS-7 cells showed that the Ala19 mutant protein showed increased cytoplasmic retention compared to wildtype, but decreased retention compared to longer expansion mutations, consistent with Ala19 being a hypomorphic allele with residual activity. Nallathambi et al. (2007) noted that Ala19 is the shortest polyalanine expansion (+5) described in the FOXL2 gene. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PREMATURE OVARIAN FAILURE 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, GLY187ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908359,
|
|
|
|
|
|
gnomAD: rs121908359,
|
|
|
|
|
|
ClinVar: RCV000005147, RCV000192031, RCV002251877, RCV003546451
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 27-year-old Tunisian patient with nonsyndromic premature ovarian failure (POF3; 608996), Laissue et al. (2009) identified heterozygosity for a c.560G-A transition in the FOXL2 gene, resulting in a gly187-to-asp (G187D) substitution in a highly conserved segment, C-terminal to the forkhead domain. The paternally inherited mutation was not found in 110 control chromosomes; it had been previously detected in an XX male (De Baere et al., 2002), but its link to that condition was unclear. Although transfection studies demonstrated normal subcellular localization of the mutant FOXL2, its transactivation capacity, which was tested on 2 reporter promoters including 1 that may be relevant to the ovary, was significantly lower than that of wildtype FOXL2. However, the G187D mutant was able to strongly activate a reporter construct driven by the OSR2 (611297) promoter, believed to be a crucial target of FOXL2 in the craniofacial region. Laissue et al. (2009) noted that this is compatible with the absence of BPES in this patient. </p></div>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXL2, GLU69LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906920,
|
|
|
|
|
|
|
|
ClinVar: RCV000023464
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a 4-generation Indian family segregating BPES type II (110100), Kaur et al. (2011) identified heterozygosity and homozygosity for a c.205G-A transition in the FOXL2 gene, resulting in a glu69-to-lys (E69K) substitution. The proband and his brother were homozygous for the mutation; both parents were heterozygous for the mutation. Their mother and a paternal aunt had classic BPES and their father had telecanthus. The disease severity in the family was found to be directly linked to the allelic dosage. </p></div>
|
|
|
|
<p>Beysen et al. (2008) found that the E69K substitution resulted in massive nuclear aggregation of FOXL2 following expression in COS-7 cells. However, the mutation had no discernible effect on transactivation of a DK3-Luc reporter gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Aparicio, S., Chapman, J., Stupka, E., Putnam, N., Chia, J., Dehal, P., Christoffels, A., Rash, S., Hoon, S., Smit, A., Gelpke, M. D. S., Roach, J., and 29 others.
|
|
<strong>Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes.</strong>
|
|
Science 297: 1301-1310, 2002.
|
|
|
|
|
|
[PubMed: 12142439]
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|
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|
|
|
[Full Text: https://doi.org/10.1126/science.1072104]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Benayoun, B. A., Batista, F., Auer, J., Dipietromaria, A., L'Hote, D., De Baere, E., Veitia, R. A.
|
|
<strong>Positive and negative feedback regulates the transcription factor FOXL2 in response to cell stress: evidence for a regulatory imbalance induced by disease-causing mutations.</strong>
|
|
Hum. Molec. Genet. 18: 632-644, 2009.
|
|
|
|
|
|
[PubMed: 19010791]
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|
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|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn389]
|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Benayoun, B. A., Caburet, S., Dipietromaria, A., Bailly-Bechet, M., Batista, F., Fellous, M., Vaiman, D., Veitia, R. A.
|
|
<strong>The identification and characterization of a FOXL2 response element provides insights into the pathogenesis of mutant alleles.</strong>
|
|
Hum. Molec. Genet. 17: 3118-3127, 2008.
|
|
|
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|
|
[PubMed: 18635577]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddn209]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Beysen, D., Moumne, L., Veitia, R., Peters, H., Leroy, B. P., De Paepe, A., De Baere, E.
|
|
<strong>Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation.</strong>
|
|
Hum. Molec. Genet. 17: 2030-2038, 2008.
|
|
|
|
|
|
[PubMed: 18372316]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddn100]
|
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Beysen, D., Raes, J., Leroy, B. P, Lucassen, A., Yates, J. R. W., Clayton-Smith, J., Ilyina, H., Sklower Brooks, S., Christin-Maitre, S., Fellous, M., Fryns, J. P., Kim, J. R., and 11 others.
|
|
<strong>Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.</strong>
|
|
Am. J. Hum. Genet. 77: 205-218, 2005.
|
|
|
|
|
|
[PubMed: 15962237]
|
|
|
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|
|
[Full Text: https://doi.org/10.1086/432083]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Beysen, D., Vandesompele, J., Messiaen, L., De Paepe, A., De Baere, E.
|
|
<strong>The human FOXL2 mutation database.</strong>
|
|
Hum. Mutat. 24: 189-193, 2004.
|
|
|
|
|
|
[PubMed: 15300845]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/humu.20079]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
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<strong>Heterozygous 17-bp deletion in the forkhead transcription factor gene, FOXL2, in a Japanese family with blepharophimosis-ptosis-epicanthus inversus syndrome.</strong>
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J. Hum. Genet. 46: 733-736, 2001.
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[PubMed: 11776388]
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[Full Text: https://doi.org/10.1007/s100380170009]
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Patricia A. Hartz - updated : 11/17/2014<br>Patricia A. Hartz - updated : 4/17/2012<br>Matthew B. Gross - updated : 3/26/2012<br>Patricia A. Hartz - updated : 3/23/2012<br>Marla J. F. O'Neill - updated : 11/15/2011<br>Jane Kelly - updated : 8/15/2011<br>Marla J. F. O'Neill - updated : 9/24/2010<br>George E. Tiller - updated : 7/7/2010<br>Patricia A. Hartz - updated : 1/29/2010<br>Joanna S. Amberger - updated : 1/25/2010<br>Patricia A. Hartz - updated : 11/4/2009<br>Marla J. F. O'Neill - updated : 10/12/2009<br>George E. Tiller - updated : 8/10/2009<br>Marla J. F. O'Neill - updated : 7/14/2009<br>George E. Tiller - updated : 4/23/2009<br>George E. Tiller - updated : 11/18/2008<br>Cassandra L. Kniffin - updated : 5/11/2007<br>Marla J. F. O'Neill - updated : 10/25/2006<br>George E. Tiller - updated : 9/6/2006<br>Marla J. F. O'Neill - updated : 8/30/2005<br>Victor A. McKusick - updated : 10/20/2004<br>Victor A. McKusick - updated : 9/30/2004<br>Deborah L. Stone - updated : 7/23/2004<br>Patricia A. Hartz - updated : 5/13/2004<br>Victor A. McKusick - updated : 1/12/2004<br>Victor A. McKusick - updated : 10/14/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 4/22/2003<br>Victor A. McKusick - updated : 2/27/2003<br>Victor A. McKusick - updated : 11/7/2002<br>Victor A. McKusick - updated : 3/6/2002<br>George E. Tiller - updated : 12/18/2001<br>Victor A. McKusick - updated : 12/3/2001
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Victor A. McKusick : 1/26/2001
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