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Entry
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- *300292 - FORKHEAD BOX P3; FOXP3
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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">*300292</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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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300292">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000049768;t=ENST00000376207" 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=50943" 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=300292" 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=ENSG00000049768;t=ENST00000376207" 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_001114377,NM_014009" 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_014009" 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=300292" 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=02242&isoform_id=02242_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/FOXP3" 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/3114818,12407641,14548061,31982943,63028441,109730459,109731678,119571056,119571057,119571058,146262391,158257536,167466190,194389696,213399772,219517996,219518921,229617483,374254777,544340138" 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/Q9BZS1" 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=50943" 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=ENSG00000049768;t=ENST00000376207" 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=FOXP3" 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=FOXP3" 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+50943" 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/FOXP3" 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:50943" 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/50943" 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=chrX&hgg_gene=ENST00000703450.1&hgg_start=49250438&hgg_end=49264710&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6106" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/foxp3" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300292[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=300292[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/FOXP3/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/ENSG00000049768" 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=FOXP3" 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=FOXP3" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://structure.bmc.lu.se/idbase/FOXP3base/" title="FOXP3base: Mutation registry for Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked; IPEX" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FOXP3base: Mutation regist…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/FOXP3" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">FOXP3 database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=FOXP3" title="CCHMC - Human Genetics Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC - Human Genetics Mut…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FOXP3&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/PA201094" 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:6106" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0262477.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1891436" 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/FOXP3#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:1891436" 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/50943/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=50943" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001439;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061116-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:50943" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FOXP3&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> 724276006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300292
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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FORKHEAD BOX P3; FOXP3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SCURFIN<br />
|
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JM2
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FOXP3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FOXP3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/X/277?start=-3&limit=10&highlight=277">Xp11.23</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:49250438-49264710&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'})">X:49,250,438-49,264,710</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
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</thead>
|
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<tbody>
|
|
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/277?start=-3&limit=10&highlight=277">
|
|
Xp11.23
|
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</a>
|
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</span>
|
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</td>
|
|
|
|
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<td>
|
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<span class="mim-font">
|
|
Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
|
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/304790"> 304790 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<p>FOXP3, a member of the fork-winged helix family of transcription factors, plays an important role in the development and function of naturally occurring CD4 (<a href="/entry/186940">186940</a>)-positive/CD25 (IL2RA; <a href="/entry/147730">147730</a>)-positive T regulatory cells (Tregs). Tregs are involved in active suppression of inappropriate immune responses (summary by <a href="#39" class="mim-tip-reference" title="Ricciardelli, I., Lindley, K. J., Londei, M., Quaratino, S. <strong>Anti tumour necrosis-alpha therapy increases the number of FOXP3(+) regulatory T cells in children affected by Crohn's disease.</strong> Immunology 125: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18422560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18422560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18422560[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2008.02839.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18422560">Ricciardelli et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18422560" 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 combining high-resolution genetic and physical mapping with large-scale sequence analysis, <a href="#6" class="mim-tip-reference" title="Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F. <strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong> Nature Genet. 27: 68-73, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>] [<a href="https://doi.org/10.1038/83784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138001">Brunkow et al. (2001)</a> identified the gene defective in 'scurfy' (sf) mice (see ANIMAL MODEL). The protein encoded by this gene, designated Foxp3, is a member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11138001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F. <strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong> Nature Genet. 27: 68-73, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>] [<a href="https://doi.org/10.1038/83784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138001">Brunkow et al. (2001)</a> compared the amino acid sequences of mouse and human scurfin with other members of the forkhead/winged-helix/HNF3 family of proteins and found the strongest similarity to the sequence of glutamine-rich factor-1 (FOXP1; <a href="/entry/605515">605515</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11138001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> stated that the human FOXP3 open reading frame of 1,146 bp encodes a deduced 381-amino acid protein. By PCR of a human peripheral blood mononuclear cell cDNA library, <a href="#44" class="mim-tip-reference" title="Smith, E. L., Finney, H. M., Nesbitt, A. M., Ramsdell, F., Robinson, M. K. <strong>Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation.</strong> Immunology 119: 203-211, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005002</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17005002[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2006.02425.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17005002">Smith et al. (2006)</a> cloned full-length FOXP3 and splice variants lacking exon 2 and both exons 2 and 7. The full-length protein contains 431 amino acids. The variant lacking exon 2 encodes a 396-amino acid protein lacking part of the proline-rich domain, and the variant lacking exons 2 and 7 encodes a 369-amino acid protein that also lacks a large part of the putative leucine zipper. <a href="#44" class="mim-tip-reference" title="Smith, E. L., Finney, H. M., Nesbitt, A. M., Ramsdell, F., Robinson, M. K. <strong>Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation.</strong> Immunology 119: 203-211, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005002</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17005002[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2006.02425.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17005002">Smith et al. (2006)</a> noted that mice appear to lack Foxp3 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17005002+11120765" 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="#6" class="mim-tip-reference" title="Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F. <strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong> Nature Genet. 27: 68-73, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>] [<a href="https://doi.org/10.1038/83784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138001">Brunkow et al. (2001)</a> determined that the mouse and human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11138001" 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="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> mapped the FOXP3 gene to chromosome Xp11.23. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" 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>Due to similarities between the autoimmunity and inflammation produced by manipulation of CD25-positive/CD4-positive regulatory T (Tr, or Treg) cells and those induced by genetic defects in the FOXP3 gene, <a href="#19" class="mim-tip-reference" title="Hori, S., Nomura, T., Sakaguchi, S. <strong>Control of regulatory T cell development by the transcription factor Foxp3.</strong> Science 299: 1057-1061, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522256</a>] [<a href="https://doi.org/10.1126/science.1079490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522256">Hori et al. (2003)</a> investigated the contribution of Foxp3 to the development and/or function of Tr cells in mice. RT-PCR analysis of normal mice showed stable, constitutive expression of Foxp3 that was high in Tr cells, low in CD4-positive/CD25-negative cells, and absent in CD4-negative/CD8 (see CD8A; <a href="/entry/186910">186910</a>)-positive T cells. Transduced expression of Foxp3 in CD4-positive/CD25-negative cells imparted a Tr phenotype in these cells, with low levels of cytokine expression, compared with nontransduced or vector-only transduced cells, and high levels of CD103 (<a href="/entry/604682">604682</a>), GITR (TNFRSF18; <a href="/entry/603905">603905</a>), and CTLA4 (<a href="/entry/123890">123890</a>). Transduced cells also showed cell-cell contact suppressive activity in vitro, as well as suppression of autoimmunity and inflammation in vivo. <a href="#19" class="mim-tip-reference" title="Hori, S., Nomura, T., Sakaguchi, S. <strong>Control of regulatory T cell development by the transcription factor Foxp3.</strong> Science 299: 1057-1061, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522256</a>] [<a href="https://doi.org/10.1126/science.1079490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522256">Hori et al. (2003)</a> proposed that FOXP3 may be a master regulatory gene and a more specific marker of Tr cells than other cell surface molecules. They also suggested that FOXP3 transduction could be a therapeutic mode for the treatment of inflammatory diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522256" 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="#45" class="mim-tip-reference" title="Stock, P., Akbari, O., Berry, G., Freeman, G. J., DeKruyff, R. H., Umetsu, D. T. <strong>Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity.</strong> Nature Immun. 5: 1149-1156, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448689</a>] [<a href="https://doi.org/10.1038/ni1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448689">Stock et al. (2004)</a> described a type of antigen-specific Tr cell that developed in vivo from naive CD4-positive/CD25-negative T cells during a Th1 polarized immune response. These Tr cells were induced by CD8A-positive dendritic cells, produced both IFNG (<a href="/entry/147570">147570</a>) and IL10 (<a href="/entry/124092">124092</a>), and expressed the Th1 'master transcription factor' TBET (TBX21; <a href="/entry/604895">604895</a>), as well as ICOS (<a href="/entry/604558">604558</a>) and FOXP3. The cells inhibited allergen-induced airway hyperreactivity in an IL10-dependent manner in mice. <a href="#45" class="mim-tip-reference" title="Stock, P., Akbari, O., Berry, G., Freeman, G. J., DeKruyff, R. H., Umetsu, D. T. <strong>Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity.</strong> Nature Immun. 5: 1149-1156, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448689</a>] [<a href="https://doi.org/10.1038/ni1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448689">Stock et al. (2004)</a> concluded that these adaptive Tr cells are related to, but distinct from, Th1 cells. They proposed that a spectrum of adaptive Tr cell types exists, comprising Th1-like cells and the previously reported Th2-like cells that are induced by CD8A-negative dendritic cells and express the Th2 'master transcription factor' GATA3 (<a href="/entry/131320">131320</a>) and FOXP3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15448689" 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 a bicistronic reporter expressing red fluorescent protein knocked in to the endogenous mouse Foxp3 locus, <a href="#49" class="mim-tip-reference" title="Wan, Y. Y., Flavell, R. A. <strong>Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter.</strong> Proc. Nat. Acad. Sci. 102: 5126-5131, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15795373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15795373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15795373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0501701102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15795373">Wan and Flavell (2005)</a> demonstrated that Foxp3 was expressed predominantly in CD4-positive/CD25-positive T cells, but also in some other CD4-positive T-cell subsets. Stimulation of activated CD4 T cells with TGFB induced both Foxp3 expression and suppressor T-cell function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15795373" 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>FOXP1, FOXP2 (<a href="/entry/605317">605317</a>), and FOXP3 all bind the FOX-binding site within the IL2 (<a href="/entry/147680">147680</a>) promoter, and all but FOXP2 suppress IL2 promoter activity. However, <a href="#5" class="mim-tip-reference" title="Bettelli, E., Dastrange, M., Oukka, M. <strong>Foxp3 interacts with nuclear factor of activated T cells and NF-kappa-B to repress cytokine gene expression and effector functions of T helper cells.</strong> Proc. Nat. Acad. Sci. 102: 5138-5143, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15790681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0501675102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790681">Bettelli et al. (2005)</a> found that forced expression of FOXP3, but not FOXP1 or FOXP2, in naive T cells suppressed not only IL2, but also IL4 (<a href="/entry/147780">147780</a>) and IFNG due to its ability to physically associate with and inhibit the cytokine gene transactivators NFKB (see <a href="/entry/164011">164011</a>) and NFAT (see <a href="/entry/600490">600490</a>). T cells derived from Foxp3-deficient scurfy mice had significantly increased Nfat and Nfkb expression, which could be lowered to physiologic levels by FOXP3 gene complementation. Transduction of myelin proteolipid protein (PLP1; <a href="/entry/300401">300401</a>)-specific autoreactive mouse T cells with FOXP3 eliminated their ability to mediate experimental autoimmune encephalomyelitis. <a href="#5" class="mim-tip-reference" title="Bettelli, E., Dastrange, M., Oukka, M. <strong>Foxp3 interacts with nuclear factor of activated T cells and NF-kappa-B to repress cytokine gene expression and effector functions of T helper cells.</strong> Proc. Nat. Acad. Sci. 102: 5138-5143, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15790681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0501675102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790681">Bettelli et al. (2005)</a> concluded that, in addition to being associated with generation of CD4-positive/CD25-positive regulatory T cells, FOXP3 acts on mature T cells by repressing NFAT and NFKB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15790681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Allan, S. E., Passerini, L., Bacchetta, R., Crellin, N., Dai, M., Orban, P. C., Ziegler, S. F., Roncarolo, M. G., Levings, M. K. <strong>The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs.</strong> J. Clin. Invest. 115: 3276-3284, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16211090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16211090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16211090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI24685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16211090">Allan et al. (2005)</a> found that, in contrast with results in mouse, overexpression of human FOXP3 alone or together with a splice variant lacking exon 2 in CD4-positive/CD25-positive regulatory T cells resulted in lower proliferation and IL2 production, but no increase in suppressive activity. <a href="#1" class="mim-tip-reference" title="Allan, S. E., Passerini, L., Bacchetta, R., Crellin, N., Dai, M., Orban, P. C., Ziegler, S. F., Roncarolo, M. G., Levings, M. K. <strong>The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs.</strong> J. Clin. Invest. 115: 3276-3284, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16211090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16211090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16211090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI24685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16211090">Allan et al. (2005)</a> suggested that factors in addition to FOXP3 are required for development of regulatory T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16211090" 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>Copolymer I (COP-I) is a random polymer of 4 amino acids (glu, lys, ala, and tyr) enriched in myelin basic protein (MBP; <a href="/entry/159430">159430</a>) that is used to treat multiple sclerosis (MS; see <a href="/entry/126200">126200</a>). <a href="#18" class="mim-tip-reference" title="Hong, J., Li, N., Zhang, X., Zheng, B., Zhang, J. Z. <strong>Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3.</strong> Proc. Nat. Acad. Sci. 102: 6449-6454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15851684[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0502187102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851684">Hong et al. (2005)</a> found that COP-I increased expression of FOXP3 in peripheral blood CD4-positive T cells of MS patients and induced conversion of CD4-positive/CD25-negative cells to CD4-positive/CD25-positive regulatory T cells. Induction of FOXP3 in CD4-positive T cells was mediated by IFNG. Mice lacking Ifng exhibited an increase in Cd4-positive/Cd25-positive cells after COP-I treatment, but these cells did not express Foxp3. <a href="#18" class="mim-tip-reference" title="Hong, J., Li, N., Zhang, X., Zheng, B., Zhang, J. Z. <strong>Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3.</strong> Proc. Nat. Acad. Sci. 102: 6449-6454, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15851684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15851684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15851684[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0502187102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15851684">Hong et al. (2005)</a> concluded that COP-I-mediated activation of FOXP3 expression and conversion of CD4-positive/CD25-negative cells to CD4-positive/CD25-positive regulatory T cells requires IFNG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15851684" 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="#44" class="mim-tip-reference" title="Smith, E. L., Finney, H. M., Nesbitt, A. M., Ramsdell, F., Robinson, M. K. <strong>Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation.</strong> Immunology 119: 203-211, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005002</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17005002[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2006.02425.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17005002">Smith et al. (2006)</a> found that overexpression of full-length FOXP3 or of the FOXP3 variants lacking exon 2 or both exons 2 and 7 reduced CD4-positive T-cell proliferation and cytokine secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17005002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Pennington, D. J., Silva-Santos, B., Silberzahn, T., Escorcio-Correia, M., Woodward, M. J., Roberts, S. J., Smith, A. L., Dyson, P. J., Hayday, A. C. <strong>Early events in the thymus affect the balance of effector and regulatory T cells.</strong> Nature 444: 1073-1077, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190001</a>] [<a href="https://doi.org/10.1038/nature06051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190001">Pennington et al. (2006)</a> showed that without any obvious effect on T cell receptor-mediated selection, the normal differentiation of mouse gamma-delta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+/CD8+ T cell progenitors to influence in trans early gamma-delta cell progenitors. Unexpectedly, <a href="#37" class="mim-tip-reference" title="Pennington, D. J., Silva-Santos, B., Silberzahn, T., Escorcio-Correia, M., Woodward, M. J., Roberts, S. J., Smith, A. L., Dyson, P. J., Hayday, A. C. <strong>Early events in the thymus affect the balance of effector and regulatory T cells.</strong> Nature 444: 1073-1077, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17190001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17190001</a>] [<a href="https://doi.org/10.1038/nature06051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17190001">Pennington et al. (2006)</a> found that the propensity of early T cell receptor alpha-beta(+) progenitors to differentiate into Foxp3+ regulatory T cells is also regulated in trans by CD4+/CD8+ T-cell progenitor cells, before agonist selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17190001" 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="Ono, M., Yaguchi, H., Ohkura, N., Kitabayashi, I., Nagamura, Y., Nomura, T., Miyachi, Y., Tsukada, T., Sakaguchi, S. <strong>Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1.</strong> Nature 446: 685-689, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17377532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17377532</a>] [<a href="https://doi.org/10.1038/nature05673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17377532">Ono et al. (2007)</a> demonstrated that the transcription factor AML1/RUNX1 (<a href="/entry/151385">151385</a>), which is crucially required for normal hematopoiesis including thymic T cell development, activates IL2 and IFN-gamma gene expression in conventional CD4+ T cells through binding to their respective promoters. In natural Treg cells, FOXP3 interacts physically with AML1. Several lines of evidence supported a model in which the interaction suppresses IL2 and IFN-gamma production, upregulates Treg cell-associated molecules, and exerts suppressive activity. <a href="#33" class="mim-tip-reference" title="Ono, M., Yaguchi, H., Ohkura, N., Kitabayashi, I., Nagamura, Y., Nomura, T., Miyachi, Y., Tsukada, T., Sakaguchi, S. <strong>Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1.</strong> Nature 446: 685-689, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17377532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17377532</a>] [<a href="https://doi.org/10.1038/nature05673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17377532">Ono et al. (2007)</a> concluded that this transcriptional control of Treg cell function by an interaction between FOXP3 and AML1 can be exploited to control physiologic and pathologic T cell-mediated immune responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17377532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Marson, A., Kretschmer, K., Frampton, G. M., Jacobsen, E. S., Polansky, J. K., Maclsaac, K. D., Levine, S. S., Fraenkel, E., von Boehmer, H., Young, R. A. <strong>Foxp3 occupancy and regulation of key target genes during T-cell stimulation.</strong> Nature 445: 931-935, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17237765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237765">Marson et al. (2007)</a> identified FOXP3 target genes and reported that many of these are key modulators of T cell activation and function. Remarkably, the predominant, although not exclusive, effect of FOXP3 occupancy is to suppress the activation of target genes on T cell stimulation. FOXP3 suppression of its targets appears to be crucial for the normal function of regulatory T cells, because overactive variants of some target genes are known to be associated with autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237765" 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="#55" class="mim-tip-reference" title="Zheng, Y., Josefowicz, S. Z., Kas, A., Chu, T.-T., Gavin, M. A., Rudensky, A. Y. <strong>Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells.</strong> Nature 445: 936-940, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237761</a>] [<a href="https://doi.org/10.1038/nature05563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237761">Zheng et al. (2007)</a> used genomewide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling to identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. The authors found that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodeling. In contrast, Foxp3 target genes shared by the thymic and peripheral regulatory T cells encode primarily plasma membrane proteins, as well as cell signaling proteins. <a href="#55" class="mim-tip-reference" title="Zheng, Y., Josefowicz, S. Z., Kas, A., Chu, T.-T., Gavin, M. A., Rudensky, A. Y. <strong>Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells.</strong> Nature 445: 936-940, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17237761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17237761</a>] [<a href="https://doi.org/10.1038/nature05563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17237761">Zheng et al. (2007)</a> concluded that distinct transcriptional subprograms implemented by Foxp3 establish regulatory T cell lineage during differentiation and its proliferative and functional competence in the periphery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17237761" 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="#57" class="mim-tip-reference" title="Zuo, T., Wang, L., Morrison, C., Chang, X., Zhang, H., Li, W., Liu, Y., Wang, Y., Liu, X., Chan, M. W. Y., Liu, J.-Q., Love, R., and 9 others. <strong>FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene.</strong> Cell 129: 1275-1286, 2007. Note: Erratum: Cell 134: 546 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17570480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17570480</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17570480[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2007.04.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17570480">Zuo et al. (2007)</a> observed that female mice heterozygous for the scurfin mutation developed cancer at a high rate. The majority of cancers were mammary carcinomas in which the wildtype Foxp3 allele was inactivated and Erbb2 (<a href="/entry/164870">164870</a>) was overexpressed. <a href="#57" class="mim-tip-reference" title="Zuo, T., Wang, L., Morrison, C., Chang, X., Zhang, H., Li, W., Liu, Y., Wang, Y., Liu, X., Chan, M. W. Y., Liu, J.-Q., Love, R., and 9 others. <strong>FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene.</strong> Cell 129: 1275-1286, 2007. Note: Erratum: Cell 134: 546 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17570480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17570480</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17570480[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2007.04.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17570480">Zuo et al. (2007)</a> found that Foxp3 repressed transcription of the Erbb2 gene via interaction with forkhead DNA-binding motifs in the Erbb2 promoter. FOXP3 expression was reduced in 10 human tumor cell lines compared with normal mammary epithelial cells and a nonmalignant cell line, and none of the tumor cell lines expressed full-length FOXP3 transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17570480" 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="#56" class="mim-tip-reference" title="Zuo, T., Liu, R., Zhang, H., Chang, X., Liu, Y., Wang, L., Zheng, P., Liu, Y. <strong>FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2.</strong> J. Clin. Invest. 117: 3765-3773, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18008005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18008005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18008005[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI32538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18008005">Zuo et al. (2007)</a> found that mouse mammary carcinomas heterozygous for a Foxp3 mutation exhibited increased Skp2 (<a href="/entry/601436">601436</a>) expression. Downregulation of FOXP3 by small interfering RNA in human mammary epithelial cells led to increased SKP2 expression. Reporter gene assays revealed that mouse Foxp3 directly interacted with and repressed the Skp2 promoter. Analysis of more than 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. <a href="#56" class="mim-tip-reference" title="Zuo, T., Liu, R., Zhang, H., Chang, X., Liu, Y., Wang, L., Zheng, P., Liu, Y. <strong>FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2.</strong> J. Clin. Invest. 117: 3765-3773, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18008005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18008005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18008005[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI32538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18008005">Zuo et al. (2007)</a> concluded that FOXP3 is an SKP2 transcriptional repressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18008005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemistry, immunofluorescence microscopy, and RT-PCR, <a href="#39" class="mim-tip-reference" title="Ricciardelli, I., Lindley, K. J., Londei, M., Quaratino, S. <strong>Anti tumour necrosis-alpha therapy increases the number of FOXP3(+) regulatory T cells in children affected by Crohn's disease.</strong> Immunology 125: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18422560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18422560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18422560[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2008.02839.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18422560">Ricciardelli et al. (2008)</a> showed that children with Crohn disease (<a href="/entry/266600">266600</a>) treated with infliximab, an anti-TNF (<a href="/entry/191160">191160</a>) antibody, had increased FOXP3-positive Tregs in their mucosa after treatment. Before treatment, FOXP3-positive T cells were reduced compared with controls. <a href="#39" class="mim-tip-reference" title="Ricciardelli, I., Lindley, K. J., Londei, M., Quaratino, S. <strong>Anti tumour necrosis-alpha therapy increases the number of FOXP3(+) regulatory T cells in children affected by Crohn's disease.</strong> Immunology 125: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18422560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18422560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18422560[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2567.2008.02839.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18422560">Ricciardelli et al. (2008)</a> concluded that infliximab not only neutralizes soluble TNF, but also affects the activation and possibly the expansion of mucosal Tregs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18422560" 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="#53" class="mim-tip-reference" title="Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., Rudensky, A. Y. <strong>Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses.</strong> Nature 458: 351-356, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19182775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19182775</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19182775[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19182775">Zheng et al. (2009)</a> showed that in mouse T regulatory cells, high amounts of interferon regulatory factor-4 (IRF4; <a href="/entry/601900">601900</a>), a transcription factor essential for TH2 effector cell differentiation, is dependent on Foxp3 expression. They proposed that IRF4 expression endows T regulatory cells with the ability to suppress TH2 responses. Indeed, ablation of a conditional Irf4 allele in T regulatory cells resulted in selective dysregulation of TH2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear cell-dominated pathology typical of mice lacking T regulatory cells. <a href="#53" class="mim-tip-reference" title="Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., Rudensky, A. Y. <strong>Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses.</strong> Nature 458: 351-356, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19182775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19182775</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19182775[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19182775">Zheng et al. (2009)</a> concluded that T regulatory cells use components of the transcriptional machinery, promoting a particular type of effector CD4+ T cell differentiation, to efficiently restrain the corresponding type of the immune response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19182775" 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="#48" class="mim-tip-reference" title="Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T., Hori, S., Fagarasan, S. <strong>Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches.</strong> Science 323: 1488-1492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286559</a>] [<a href="https://doi.org/10.1126/science.1169152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286559">Tsuji et al. (2009)</a> demonstrated that suppressive Foxp3+CD4+ T cells can differentiate into follicular B helper T cells (T-FH) in mouse Peyer patches. The conversion of Foxp3+ T cells into T-FH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, <a href="#48" class="mim-tip-reference" title="Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T., Hori, S., Fagarasan, S. <strong>Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches.</strong> Science 323: 1488-1492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19286559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19286559</a>] [<a href="https://doi.org/10.1126/science.1169152" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19286559">Tsuji et al. (2009)</a> concluded that environmental cues present in gut Peyer patches promote the selective differentiation of distinct helper T cell subsets, such as T-FH cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19286559" 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="#14" class="mim-tip-reference" title="Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., Lee, J., Goldfine, A. B., Benoist, C., Shoelson, S., Mathis, D. <strong>Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.</strong> Nature Med. 15: 930-939, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633656</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19633656[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633656">Feuerer et al. (2009)</a> examined Treg cells in mouse abdominal adipose tissue and found that more than half of the CD4(+) T cells expressed Foxp3, a much higher fraction than normally seen even in subcutaneous fat; and there was progressive accumulation of CD4(+)/Foxp3(+) Treg cells over time in the visceral, but not the subcutaneous, depot. Comparison of the documented Treg cell signature with that of Treg cells from abdominal fat revealed that many of the signature Treg cell genes were not significantly up- or downregulated in the corresponding population from visceral fat. This unique population of Treg cells was specifically reduced in abdominal fat in insulin-resistant mouse models of obesity, and loss- and gain-of-function experiments revealed that these Treg cells influenced the inflammatory state of adipose tissue and, therefore, insulin resistance. Cytokines differentially synthesized by fat-resident Treg and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. Analysis of paired frozen omental and subcutaneous fat tissues from individuals with body mass indices (BMIs) in the obese to morbidly obese range showed a correlation between BMI and the drop in Treg cells in omental versus subcutaneous fat. <a href="#14" class="mim-tip-reference" title="Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A., Wong, J., Nayer, A., Lee, J., Goldfine, A. B., Benoist, C., Shoelson, S., Mathis, D. <strong>Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.</strong> Nature Med. 15: 930-939, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19633656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19633656</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19633656[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19633656">Feuerer et al. (2009)</a> concluded that CD4(+)/FOXP3(+) Treg cells play a role in metabolic homeostasis and in its dysregulation in obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19633656" 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="Pan, F., Yu, H., Dang, E. V., Barbi, J., Pan, X., Grosso, J. F., Jinasena, D., Sharma, S. M., McCadden, E. M., Getnet, D., Drake, C. G., Liu, J. O., Ostrowski, M. C., Pardoll, D. M. <strong>Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.</strong> Science 325: 1142-1146, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19696312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19696312</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19696312[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1176077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19696312">Pan et al. (2009)</a> identified Eos (<a href="/entry/606239">606239</a>), a zinc finger transcription factor of the Ikaros family, as a critical mediator of FOXP3-dependent gene silencing in Tregs. Eos interacted directly with FOXP3 and induced chromatin modifications that resulted in gene silencing in Tregs. <a href="#35" class="mim-tip-reference" title="Pan, F., Yu, H., Dang, E. V., Barbi, J., Pan, X., Grosso, J. F., Jinasena, D., Sharma, S. M., McCadden, E. M., Getnet, D., Drake, C. G., Liu, J. O., Ostrowski, M. C., Pardoll, D. M. <strong>Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.</strong> Science 325: 1142-1146, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19696312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19696312</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19696312[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1176077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19696312">Pan et al. (2009)</a> found that silencing of Eos in Tregs abrogated their ability to suppress immune responses and endowed them with partial effector function, thus demonstrating the critical role that Eos plays in Treg programming. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19696312" 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>FOXP3-positive Treg cells occasionally lose their suppressive phenotype to perform a helper-like role without losing expression of FOXP3. <a href="#42" class="mim-tip-reference" title="Sharma, M. D., Huang, L., Choi, J.-H., Lee, E.-J., Wilson, J. M., Lemos, H., Pan, F., Blazar, B. R., Pardoll, D. M., Mellor, A. L., Shi, H., Munn, D. H. <strong>An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor Eos.</strong> Immunity 38: 998-1012, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684987">Sharma et al. (2013)</a> showed that reprogramming of mouse Treg cells was controlled by Il6 (<a href="/entry/147620">147620</a>)-dependent downregulation of Eos. Treatment of Foxp3-positive Treg cells with cycloheximide showed that most retained Eos expression (i.e., they were Eos-stable), whereas a Cd38 (<a href="/entry/107270">107270</a>)-positive subset rapidly lost Eos expression (i.e., they were Eos-labile) with no change in Foxp3 expression. Thymic Treg cells from Il6 -/- mice did not express Cd38 and did not have an Eos-labile subset. Successful vaccination of naive mice required the Cd38-positive/Eos-labile subset of Treg cells. However, immunodeficient mice were fully protected from colitis by both Eos-stable and Eos-labile Treg cells. Epigenetic analysis of spleen and thymus Treg cells revealed significant differences in methylation between Eos-labile and Eos-stable cells. Eos downregulation was prevented by tumor-induced Ido (<a href="/entry/147435">147435</a>). <a href="#42" class="mim-tip-reference" title="Sharma, M. D., Huang, L., Choi, J.-H., Lee, E.-J., Wilson, J. M., Lemos, H., Pan, F., Blazar, B. R., Pardoll, D. M., Mellor, A. L., Shi, H., Munn, D. H. <strong>An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor Eos.</strong> Immunity 38: 998-1012, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684987</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684987[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.immuni.2013.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684987">Sharma et al. (2013)</a> concluded that the Eos corepressor defines 2 sets of FOXP3-positive Treg cells, one that is stably suppressive and the other a labile one that is available in certain circumstances to provide helper activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23684987" 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 flow cytometric analysis, <a href="#7" class="mim-tip-reference" title="Casetti, R., Agrati, C., Wallace, M., Sacchi, A., Martini, F., Martino, A., Rinaldi, A., Malkovsky, M. <strong>Cutting edge: TGF-beta-1 and IL-15 induce FOXP3(+) gamma-delta regulatory T cells in the presence of antigen stimulation.</strong> J. Immun. 183: 3574-3577, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710458</a>] [<a href="https://doi.org/10.4049/jimmunol.0901334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19710458">Casetti et al. (2009)</a> demonstrated that, like alpha-beta T cells, gamma-delta cells can also function as Tregs that express FOXP3 when stimulated with phosphoantigen in the presence of TGFB1 (<a href="/entry/190180">190180</a>) and IL15 (<a href="/entry/600554">600554</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19710458" 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="#54" class="mim-tip-reference" title="Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X. P., Forbush, K., Rudensky, A. Y. <strong>Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.</strong> Nature 463: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072126">Zheng et al. (2010)</a> described the function of 3 Foxp3 conserved noncoding DNA sequence (CNS) elements termed CNS1-3 in T regulatory cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T regulatory cells generated in the thymus and the periphery, binds c-Rel (<a href="/entry/164910">164910</a>) in in vitro assays. In contrast, CNS1, which contains a TGF-beta (<a href="/entry/190180">190180</a>)-NFAT (see <a href="/entry/600489">600489</a>) response element, is superfluous for thymic T regulatory cell differentiation, but has a prominent role in periphery T regulatory cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T regulatory cells. Foxp3 binds to CNS2 in a Cbf-beta (<a href="/entry/121360">121360</a>)-Runx1 (<a href="/entry/151385">151385</a>) and CpG DNA demethylation-dependent manner, suggesting that FOXP3 recruitment to this cellular memory module facilitates the heritable maintenance of the active state of the FOXP3 locus and, therefore, T regulatory lineage stability. <a href="#54" class="mim-tip-reference" title="Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X. P., Forbush, K., Rudensky, A. Y. <strong>Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.</strong> Nature 463: 808-812, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20072126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20072126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20072126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20072126">Zheng et al. (2010)</a> concluded that their studies demonstrated that the composition, size, and maintenance of the T regulatory cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20072126" 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>Human T-lymphotropic virus (HTLV)-1 is a persistent retrovirus estimated to infect 10 to 20 million people. The majority of infected individuals are asymptomatic carriers, but 1 to 3% of infected individuals develop progressive inflammation of the central nervous system (see <a href="/entry/159580">159580</a>), and about 4% of seropositive individuals develop a malignant lymphoproliferative disorder called adult T-cell leukemia/lymphoma (ATLL). <a href="#47" class="mim-tip-reference" title="Toulza, F., Nosaka, K., Tanaka, Y., Schioppa, T., Balkwill, F., Taylor, G. P., Bangham, C. R. M. <strong>Human T-lymphotropic virus type 1-induced CC chemokine ligand 22 maintains a high frequency of functional FoxP3+ regulatory T cells.</strong> J. Immun. 185: 183-189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20525891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20525891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20525891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.4049/jimmunol.0903846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20525891">Toulza et al. (2010)</a> found that there was a high concentration of plasma CCL22 (<a href="/entry/602957">602957</a>) in HTLV-1-infected individuals and that the concentration was strongly correlated with the frequency of FOXP3-positive cells, which express the CCL22 receptor CCR4 (<a href="/entry/604836">604836</a>). CCL22 was produced by cells that expressed the HTLV-1 transactivator protein Tax, and the increased CCL22 enhanced the migration and survival of FOXP3-positive cells in vitro. <a href="#47" class="mim-tip-reference" title="Toulza, F., Nosaka, K., Tanaka, Y., Schioppa, T., Balkwill, F., Taylor, G. P., Bangham, C. R. M. <strong>Human T-lymphotropic virus type 1-induced CC chemokine ligand 22 maintains a high frequency of functional FoxP3+ regulatory T cells.</strong> J. Immun. 185: 183-189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20525891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20525891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20525891[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.4049/jimmunol.0903846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20525891">Toulza et al. (2010)</a> concluded that HTLV-1-induced CCL22 causes the high frequency of FOXP3-positive cells observed in HTLV-1 infection and that FOXP3-positive cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20525891" 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 RT-PCR and flow cytometric analysis, <a href="#31" class="mim-tip-reference" title="Miura, Y., Thoburn, C. J., Bright, E. C., Phelps, M. L., Shin, T., Matsui, E. C., Matsui, W. H., Arai, S., Fuchs, E. J., Vogelsang, G. B., Jones, R. J., Hess, A. D. <strong>Association of Foxp3 regulatory gene expression with graft-versus-host disease.</strong> Blood 104: 2187-2193, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15172973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15172973</a>] [<a href="https://doi.org/10.1182/blood-2004-03-1040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15172973">Miura et al. (2004)</a> showed that the cytokine storm associated with graft-versus-host disease (GVHD; see <a href="/entry/614395">614395</a>) correlated with decreased FOXP3 expression in mononuclear cells of bone marrow transplant patients. FOXP3 expression was higher in patients without GVHD. FOXP3 expression positively correlated with the presence of recent thymic emigrants. <a href="#31" class="mim-tip-reference" title="Miura, Y., Thoburn, C. J., Bright, E. C., Phelps, M. L., Shin, T., Matsui, E. C., Matsui, W. H., Arai, S., Fuchs, E. J., Vogelsang, G. B., Jones, R. J., Hess, A. D. <strong>Association of Foxp3 regulatory gene expression with graft-versus-host disease.</strong> Blood 104: 2187-2193, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15172973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15172973</a>] [<a href="https://doi.org/10.1182/blood-2004-03-1040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15172973">Miura et al. (2004)</a> suggested that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms after transplantation, and that decreased regulatory mechanisms provide an environment that permits development of GVHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15172973" 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 flow cytometric analysis to identify Treg frequencies in 32 blood donors with acute West Nile virus (WNV; see <a href="/entry/610379">610379</a>) infection, <a href="#25" class="mim-tip-reference" title="Lanteri, M. C., O'Brien, K. M., Purtha, W. E., Cameron, M. J., Lund, J. M., Owen, R. E., Heitman, J. W., Custer, B., Hirschkorn, D. F., Tobler, L. H., Kiely, N., Prince, H. E., Ndhlovu, L. C., Nixon, D. F., Kamel, H. T., Kelvin, D. J., Busch, M. P., Rudensky, A. Y., Diamond, M. S., Norris, P. J. <strong>Tregs control the development of symptomatic West Nile virus infection in humans and mice.</strong> J. Clin. Invest. 119: 3266-3277, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19855131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19855131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19855131[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI39387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19855131">Lanteri et al. (2009)</a> demonstrated that CD4-positive/FOXP3-positive Treg frequencies increased in all individuals in the 3 months after the index donation that revealed WNV RNA in plasma. However, symptomatic donors exhibited lower Treg frequencies up to 1 year after index donation without showing systemic T-cell or generalized inflammatory responses. Studies in WNV-infected mice showed that symptomatic mice displayed lower Treg frequencies than asymptomatic mice. Moreover, mice lacking Foxp3-positive Tregs experienced increased lethality following WNV infection compared with controls. <a href="#25" class="mim-tip-reference" title="Lanteri, M. C., O'Brien, K. M., Purtha, W. E., Cameron, M. J., Lund, J. M., Owen, R. E., Heitman, J. W., Custer, B., Hirschkorn, D. F., Tobler, L. H., Kiely, N., Prince, H. E., Ndhlovu, L. C., Nixon, D. F., Kamel, H. T., Kelvin, D. J., Busch, M. P., Rudensky, A. Y., Diamond, M. S., Norris, P. J. <strong>Tregs control the development of symptomatic West Nile virus infection in humans and mice.</strong> J. Clin. Invest. 119: 3266-3277, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19855131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19855131</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19855131[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI39387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19855131">Lanteri et al. (2009)</a> concluded that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19855131" 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="Liu, B., Tahk, S., Yee, K. M., Fan, G., Shuai, K. <strong>The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.</strong> Science 330: 521-525, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20966256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20966256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20966256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1193787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20966256">Liu et al. (2010)</a> reported that the SUMO E3 ligase PIAS1 (<a href="/entry/603566">603566</a>) restricts the differentiation of natural T regulatory cells by maintaining a repressive chromatin state of the FOXP3 promoter. PIAS1 acts by binding to the FOXP3 promoter to recruit DNA methyltransferases and heterochromatin protein-1 (CBX5; <a href="/entry/604478">604478</a>) for epigenetic modifications. PIAS1 deletion caused promoter demethylation, reduced histone H3 methylation (see <a href="/entry/602810">602810</a>) at lys9, and enhanced promoter accessibility. Consistently, Pias1-null mice displayed an increased natural T regulatory cell population and were resistant to the development of experimental autoimmune encephalomyelitis. <a href="#27" class="mim-tip-reference" title="Liu, B., Tahk, S., Yee, K. M., Fan, G., Shuai, K. <strong>The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.</strong> Science 330: 521-525, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20966256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20966256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20966256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1193787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20966256">Liu et al. (2010)</a> concluded that their studies identified an epigenetic mechanism that negatively regulates the differentiation of natural T regulatory cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20966256" 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>Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argued instead for the developmentally ordered appearance (or 'layering') of distinct HSCs that give rise to distinct lymphocyte lineages at different stages of development. <a href="#32" class="mim-tip-reference" title="Mold, J. E., Venkatasubrahmanyam, S., Burt, T. D., Michaelsson, J., Rivera, J. M., Galkina, S. A., Weinberg, K., Stoddart, C. A., McCune, J. M. <strong>Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans.</strong> Science 330: 1695-1699, 2010. Note: Erratum: Science 331: 534 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21164017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21164017</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21164017[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1196509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21164017">Mold et al. (2010)</a> provided evidence of an analogous layered immune system in humans. <a href="#32" class="mim-tip-reference" title="Mold, J. E., Venkatasubrahmanyam, S., Burt, T. D., Michaelsson, J., Rivera, J. M., Galkina, S. A., Weinberg, K., Stoddart, C. A., McCune, J. M. <strong>Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans.</strong> Science 330: 1695-1699, 2010. Note: Erratum: Science 331: 534 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21164017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21164017</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21164017[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1196509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21164017">Mold et al. (2010)</a> investigated whether fetal and adult HSPCs might differ in their capacity to generate Tregs in the thymus, because fetal T cells appear to be predisposed to generating Foxp3+ Tregs upon stimulation in vitro, and there is an abundance of Tregs in the peripheral tissues of midgestation fetuses. Both fetal liver- and fetal bone marrow-derived HSPCs were found to generate populations of CD25+Foxp3+ SP4 thymocytes. Thus it appeared that fetal HSPCs display a heightened capacity to generate Tregs during thymic maturation. <a href="#32" class="mim-tip-reference" title="Mold, J. E., Venkatasubrahmanyam, S., Burt, T. D., Michaelsson, J., Rivera, J. M., Galkina, S. A., Weinberg, K., Stoddart, C. A., McCune, J. M. <strong>Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans.</strong> Science 330: 1695-1699, 2010. Note: Erratum: Science 331: 534 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21164017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21164017</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21164017[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1196509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21164017">Mold et al. (2010)</a> provided evidence that the fetal T cell lineage is biased toward immune tolerance. They concluded that their observations offered a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21164017" 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 predominantly wildtype and Hif1a (<a href="/entry/603348">603348</a>)-/- mouse T cells, <a href="#11" class="mim-tip-reference" title="Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., Pan, F. <strong>Control of TH17/T-reg balance by hypoxia-inducible factor 1.</strong> Cell 146: 772-784, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21871655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21871655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21871655[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2011.07.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21871655">Dang et al. (2011)</a> showed that Hif1a was specifically required for differentiation of naive T cells into interleukin-17 (IL17; <a href="/entry/603149">603149</a>)-expressing helper T (Th) cells. Hif1a interacted directly with Ror-gamma-t (RORC; <a href="/entry/602943">602943</a>) and acetyltransferase p300 (EP300; <a href="/entry/602700">602700</a>) at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into Treg cells by directing proteasomal degradation of Foxp3 by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (<a href="/entry/159465">159465</a>)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. <a href="#11" class="mim-tip-reference" title="Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., Pan, F. <strong>Control of TH17/T-reg balance by hypoxia-inducible factor 1.</strong> Cell 146: 772-784, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21871655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21871655</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21871655[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2011.07.033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21871655">Dang et al. (2011)</a> concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21871655" 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>Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3+ regulatory T cells (Treg cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. <a href="#41" class="mim-tip-reference" title="Rowe, J. H., Ertelt, J. M., Xin, L., Way, S. S. <strong>Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.</strong> Nature 490: 102-106, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23023128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23023128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23023128[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23023128">Rowe et al. (2012)</a> showed that pregnancy selectively stimulates the accumulation of maternal FOXP3+ CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific Treg cells persist at elevated levels, maintain tolerance to preexisting fetal antigen, and rapidly reaccumulate during subsequent pregnancy. The accelerated expansion of Treg cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3+ cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of preexisting FOXP3+ cells each contribute to Treg expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3+ cell ablation. Thus, <a href="#41" class="mim-tip-reference" title="Rowe, J. H., Ertelt, J. M., Xin, L., Way, S. S. <strong>Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.</strong> Nature 490: 102-106, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23023128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23023128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23023128[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature11462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23023128">Rowe et al. (2012)</a> concluded that pregnancy imprints FOXP3+ CD4 cells that sustain protective regulatory memory to fetal antigen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23023128" 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 yeast 2-hybrid and coimmunoprecipitation analyses, <a href="#20" class="mim-tip-reference" title="Huang, C., Martin, S., Pfleger, C., Du, J., Buckner, J. H., Bluestone, J. A., Riley, J. L., Ziegler, S. F. <strong>Cutting edge: a novel, human-specific interacting protein couples FOXP3 to a chromatin-remodeling complex that contains KAP1/TRIM28.</strong> J. Immun. 190: 4470-4473, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23543754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23543754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23543754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.4049/jimmunol.1203561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23543754">Huang et al. (2013)</a> showed that the proline-rich N terminus of FOXP3 interacted with the C terminus of FIK, an isoform of ZFP90 (<a href="/entry/609451">609451</a>). They noted that this region of FOXP3 also interacts with IKZF4 and KAT5 (<a href="/entry/601409">601409</a>), suggesting that it is involved in regulating repressive chromatin-remodeling complexes. Expression of FOXP3 and FIK in Jurkat T cells led to decreased expression of IL2 and IFNG, and chromatin immunoprecipitation analysis showed that FOXP3, FIK, and KAP1, which binds to the A box within the KRAB domain of FIK, were present on the same site on the IL2 and IFNG promoters. FIK was highly expressed in Tregs, and disruption of the FOXP3-FIK-KAP1 complex in Tregs abrogated their suppressor activity. <a href="#20" class="mim-tip-reference" title="Huang, C., Martin, S., Pfleger, C., Du, J., Buckner, J. H., Bluestone, J. A., Riley, J. L., Ziegler, S. F. <strong>Cutting edge: a novel, human-specific interacting protein couples FOXP3 to a chromatin-remodeling complex that contains KAP1/TRIM28.</strong> J. Immun. 190: 4470-4473, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23543754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23543754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23543754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.4049/jimmunol.1203561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23543754">Huang et al. (2013)</a> concluded that FIK has a critical role in regulating FOXP3 activity and Treg function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23543754" 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="#43" class="mim-tip-reference" title="Smigiel, K. S., Richards, E., Srivastava, S., Thomas, K. R., Dudda, J. C., Klonowski, K. D., Campbell, D. J. <strong>CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets.</strong> J. Exp. Med. 211: 121-136, 2014. Note: Erratum: J. Exp. Med. 216: 1965 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24378538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24378538</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24378538[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20131142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24378538">Smigiel et al. (2014)</a> noted that FOXP3-positive Tregs depend on IL2 (<a href="/entry/147680">147680</a>) for maintaining tolerance and preventing autoimmunity. They showed that mouse central Tregs (cTregs), which express low levels of Cd44 (<a href="/entry/107269">107269</a>) and high levels of Cd62l (SELL; <a href="/entry/153240">153240</a>) (i.e., Cd44-lo/Cd62l-hi), were quiescent and long-lived. In contrast, mouse effector Tregs (eTregs), which are Cd44-hi/Cd62l-lo, differentiated from cTregs and underwent rapid proliferation that was balanced by a high rate of apoptotic cell death. Although eTregs expressed lower levels of Cd25, they responded well to Il2. cTregs gained access to paracrine Il2 through their expression of Ccr7 (<a href="/entry/600242">600242</a>), whereas eTregs populating nonlymphoid tissues expressed low Ccr7, did not access Il2-prevalent regions in vivo, and were insensitive to Il2 blockade. eTregs were maintained by signaling through Icos. <a href="#43" class="mim-tip-reference" title="Smigiel, K. S., Richards, E., Srivastava, S., Thomas, K. R., Dudda, J. C., Klonowski, K. D., Campbell, D. J. <strong>CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets.</strong> J. Exp. Med. 211: 121-136, 2014. Note: Erratum: J. Exp. Med. 216: 1965 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24378538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24378538</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24378538[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20131142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24378538">Smigiel et al. (2014)</a> concluded that there is a fundamental homeostatic subdivision in Treg populations based on their localization and signaling mechanisms in different environments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24378538" 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 mice, <a href="#12" class="mim-tip-reference" title="Feng, Y., van der Veeken, J., Shugay, M., Putintseva, E. V., Osmanbeyoglu, H. U., Dikiy, S., Hoyos, B. E., Moltedo, B., Hemmers, S., Treuting, P., Leslie, C. S., Chudakov, D. M., Rudensky, A. Y. <strong>A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.</strong> Nature 528: 132-136, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26605529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26605529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26605529[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26605529">Feng et al. (2015)</a> explored whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. <a href="#12" class="mim-tip-reference" title="Feng, Y., van der Veeken, J., Shugay, M., Putintseva, E. V., Osmanbeyoglu, H. U., Dikiy, S., Hoyos, B. E., Moltedo, B., Hemmers, S., Treuting, P., Leslie, C. S., Chudakov, D. M., Rudensky, A. Y. <strong>A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance.</strong> Nature 528: 132-136, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26605529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26605529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26605529[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26605529">Feng et al. (2015)</a> showed that the intronic Foxp3 enhancer conserved noncoding sequence-3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26605529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Hang, S., Paik, D., Yao, L., Kim, E., Trinath, J., Lu, J., Ha, S., Nelson, B. N., Kelly, S. P., Wu, L., Zheng, Y., Longman, R. S., Rastinejad, F., Devlin, A. S., Krout, M. R., Fischbach, M. A., Littman, D. R., Huh, J. R. <strong>Bile acid metabolites control TH17 and Treg cell differentiation.</strong> Nature 576: 143-148, 2019. Note: Erratum: Nature 579: E7, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31776512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31776512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31776512[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1785-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31776512">Hang et al. (2019)</a> screened a library of bile acid metabolites and identified 2 distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of Th17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-gamma-t (ROR-gamma-t; <a href="/entry/602943">602943</a>) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS)3; this represented a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced Th17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. <a href="#17" class="mim-tip-reference" title="Hang, S., Paik, D., Yao, L., Kim, E., Trinath, J., Lu, J., Ha, S., Nelson, B. N., Kelly, S. P., Wu, L., Zheng, Y., Longman, R. S., Rastinejad, F., Devlin, A. S., Krout, M. R., Fischbach, M. A., Littman, D. R., Huh, J. R. <strong>Bile acid metabolites control TH17 and Treg cell differentiation.</strong> Nature 576: 143-148, 2019. Note: Erratum: Nature 579: E7, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31776512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31776512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31776512[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1785-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31776512">Hang et al. (2019)</a> concluded that their data suggested mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of Th17 and Treg cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31776512" 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 a CRISPR-based loss-of-function screen in mouse regulatory T cells (Tregs), <a href="#10" class="mim-tip-reference" title="Cortez, J. T., Montauti, E., Shifrut, E., Gatchalian, J., Zhang, Y., Shaked, O., Xu, Y., Roth, T. L., Simeonov, D. R., Zhang, Y., Chen, S., Li, Z., and 13 others. <strong>CRISPR screen in regulatory T cells reveals modulators of Foxp3.</strong> Nature 582: 416-420, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32499641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32499641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32499641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2246-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32499641">Cortez et al. (2020)</a> identified several modulators of Foxp3 expression, including the deubiquitinase Usp22 (<a href="/entry/612116">612116</a>) as a positive regulator of Foxp3, and the E3 ubiquitin ligase Rnf20 (<a href="/entry/607699">607699</a>) as a negative regulator. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in Treg suppressive function, resulting in spontaneous autoimmunity and protection against tumor growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Tregs could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Tregs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32499641" 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>Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The regression and eventual termination of GCs are factors that ultimately limit the extent to which antibodies mature within a single reaction. <a href="#21" class="mim-tip-reference" title="Jacobsen, J. T., Hu, W., Castro, T. B. R., Solem, S., Galante, A., Lin, Z., Allon, S. J., Mesin, L., Bilate, A. M., Schiepers, A., Shalek, A. K., Rudensky, A. Y., Victora, G. D. <strong>Expression of Foxp3 by T follicular helper cells in end-stage germinal centers.</strong> Science 373: eabe5146, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34437125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34437125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34437125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.abe5146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34437125">Jacobsen et al. (2021)</a> demonstrated that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to upregulation of the transcription factor Foxp3 by T follicular helper (TFH) cells. Ectopic expression of Foxp3 in TFH cells is sufficient to decrease GC size, implicating the natural upregulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34437125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using pull-down assays, <a href="#52" class="mim-tip-reference" title="Zhang, W., Leng, F., Wang, X., Ramirez, R. N., Park, J., Benoist, C., Hur, S. <strong>FOXP3 recognizes microsatellites and bridges DNA through multimerization.</strong> Nature 624: 433-441, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38030726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38030726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38030726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-023-06793-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38030726">Zhang et al. (2023)</a> demonstrated that purified recombinant mouse Foxp3 bound genomic DNA containing T(n)G (where n = 2 through 5) repeat-like sequences. T(n)G repeat-like elements were important for the interaction, and Foxp3 bound only a small fraction of T(n)G repeat-like sequences in accessible functional sites for transcriptional regulation, despite the widespread presence of T(n)G repeat-like sequences in the mouse genome. Foxp3 multimerized on T(n)G repeats. The cryoelectron microscopy structure of Foxp3 in a complex with a T(3)G 18-mer repeat revealed a ladder-like architecture, whereby 2 double-stranded DNA molecules formed the 2 'side rails,' bridged by 5 pairs of Foxp3 molecules, with each pair forming a 'rung' through interaction between 2 Foxp3 protein molecules (intra-rung interactions). Each Foxp3 subunit occupied TGTTTGT within the repeats in a manner that was indistinguishable from that of Foxp3 bound to the forkhead consensus motif (TGTTTAC). DNA bridging between T(n)G repeats was present in solution, and Foxp3 multimerization on T(n)G repeats contributed to long-distance chromatin contacts in Treg cells. Mutations in the intra-rung interface impaired T(n)G repeat recognition, DNA bridging, and Foxp3 cellular functions, without affecting binding to the forkhead consensus motif. The rungs were separated by 8 bp or 12 bp in an alternating manner, forming 2 different types of inter-rung interactions. The inter-rung 8-bp interaction was a strong-ordered interaction, whereas the inter-rung 12-bp interaction appeared to be weak or less-ordered, allowing Foxp3 to tolerate variable inter-rung spacings and confer a broad specificity for T(n)G-repeat-like sequences. The T(n)G repeat binding was conserved, as both Foxp3 orthologs and paralogs showed similar T(N)G repeat recognition and DNA bridging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38030726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a>, who referred to the FOXP3 gene as JM2, identified it by the positional-candidate approach as the likely site of mutations in the disorder they referred to as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) and known by others as IPEX (<a href="/entry/304790">304790</a>). <a href="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> detected a mutation in the FOXP3 gene in 2 unrelated kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" 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="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> sequenced the human FOXP3 gene to determine whether the X-linked syndrome of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is the human equivalent of the scurfy mouse. They identified a novel mutation in each proband from 4 families with IPEX. Each mutation affected the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions. In a fifth family studied by <a href="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> in which a variant form of IPEX mapped to the pericentromeric region of the X chromosome, no mutation in the FOXP3 gene was found. A later age of onset, waxing and waning clinical course, and occasional compatibility with prolonged survival had been reported in this family (<a href="#38" class="mim-tip-reference" title="Powell, B. R., Buist, N. R. M., Stenzel, P. <strong>An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.</strong> J. Pediat. 100: 731-737, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7040622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7040622</a>] [<a href="https://doi.org/10.1016/s0022-3476(82)80573-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7040622">Powell et al., 1982</a>). This contrasted with the early, unrelenting course of the disorder seen in the other families. <a href="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> suggested that this fifth family may harbor a noncoding FOXP3 mutation that affects transcriptional regulation or RNA splicing, resulting in a milder, environmentally dependent phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11137992+7040622" 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="Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D. <strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong> Nature Genet. 27: 20-21, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137993</a>] [<a href="https://doi.org/10.1038/83713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137993">Bennett et al. (2001)</a> also identified mutations in the FOXP3 gene in IPEX patients. They compared the mutations in FOXP3 with those in FOXE1 (<a href="/entry/602617">602617</a>) which result in a thyroid agenesis syndrome, and with those in FOXC1 (<a href="/entry/601090">601090</a>) which cause malformation of the anterior segment of the eye (Axenfeld-Rieger anomaly). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bassuny, W. M., Ihara, K., Sasaki, Y., Kuromaru, R., Kohno, H., Matsuura, N., Hara, T. <strong>A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes.</strong> Immunogenetics 55: 149-156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750858</a>] [<a href="https://doi.org/10.1007/s00251-003-0559-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750858">Bassuny et al. (2003)</a> investigated the FOXP3 gene as a candidate for the type I diabetes susceptibility locus IDDMX (<a href="/entry/300136">300136</a>). They screened the FOXP3 gene for microsatellite and single nucleotide polymorphisms and performed an association study between the gene and type I diabetes in the Japanese population. One microsatellite polymorphism, (GT)n, was identified in intron 0, and a (GT)15 allele showed a significantly higher frequency in patients with type I diabetes than in controls (43.1% vs 32.6%, P = 0.0027). The evaluation of promoter/enhancer activity of the (GT)n polymorphism was performed by dual luciferase reporter assay. A significant difference in the enhancer activity between (GT)15 and (GT)16 dinucleotide repeats was detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750858" 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="Owen, C. J., Jennings, C. E., Imrie, H., Lachaux, A., Bridges, N. A., Cheetham, T. D., Pearce, S. H. S. <strong>Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome.</strong> J. Clin. Endocr. Metab. 88: 6034-6039, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671208</a>] [<a href="https://doi.org/10.1210/jc.2003-031080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14671208">Owen et al. (2003)</a> studied 2 kindreds (21 subjects total) with 4 male infants (3 deceased) and 1 girl affected by IPEX. In 1 of the families they found a novel frameshift mutation in the FOXP3 gene (<a href="#0008">300292.0008</a>). In the second family, the FOXP3 locus was excluded by recombination, and no FOXP3 mutations were found. They concluded that their data provided evidence for a nonlinked autosomal locus, suggesting genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671208" 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="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a> studied the phenotype and in vitro function of CD4-positive T cells and CD4-positive/CD25(high) Treg cells in 4 children with IPEX. Flow cytometric analysis demonstrated that distribution and expression of various T-cell markers was comparable between patients and normal donor controls. Patient Treg cells showed different degrees of suppressive activity depending on the FOXP3 mutation, but none of the patients cells could suppress autologous responder cells. The defect was overcome after in vitro expansion of Treg cells. Of the 4 IPEX patients, only 1, who had a mutation in codon 1 (<a href="#0012">300292.0012</a>) that resulted in no protein expression, had impaired transcription or translation of FOXP3. All patients had normal proliferative responses after T-cell receptor (TCR) stimulation, but they were unable to produce IL2 or IFNG. <a href="#2" class="mim-tip-reference" title="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a> concluded that Treg cells can be present in normal numbers in IPEX patients, but their capacity to suppress is impaired depending on the type of mutation, the strength of TCR stimuli, and the genotype of the effector T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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>'Scurfy' (sf) is an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth, and is characterized by overproliferation of CD4+/CD8- T lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines (<a href="#29" class="mim-tip-reference" title="Lyon, M. F., Peters, J., Glenister, P. H., Ball, S., Wright, E. <strong>The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.</strong> Proc. Nat. Acad. Sci. 87: 2433-2437, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2320565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2320565</a>] [<a href="https://doi.org/10.1073/pnas.87.7.2433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2320565">Lyon et al., 1990</a>; <a href="#9" class="mim-tip-reference" title="Clark, L. B., Appleby, M. W., Brunkow, M. E., Wilkinson, J. E., Ziegler, S. F., Ramsdell, F. <strong>Cellular and molecular characterization of the scurfy mouse mutant.</strong> J. Immun. 162: 2546-2554, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072494</a>]" pmid="10072494">Clark et al., 1999</a>). Similar to animals that lack expression of either Ctla4 (<a href="/entry/123890">123890</a>) or Tgf-beta (TGFB1; <a href="/entry/190180">190180</a>), the pathology observed in sf mice seems to result from an inability to regulate properly CD4+/CD8- T-cell activity. <a href="#6" class="mim-tip-reference" title="Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F. <strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong> Nature Genet. 27: 68-73, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>] [<a href="https://doi.org/10.1038/83784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138001">Brunkow et al. (2001)</a> determined that the Foxp3 gene is mutant in sf mice. A frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10072494+11138001+2320565" 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 mice overexpressing the Foxp3 gene, <a href="#23" class="mim-tip-reference" title="Khattri, R., Kasprowicz, D., Cox, T., Mortrud, M., Appleby, M. W., Brunkow, M. E., Ziegler, S. F., Ramsdell, F. <strong>The amount of scurfin protein determines peripheral T cell number and responsiveness.</strong> J. Immun. 167: 6312-6320, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11714795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11714795</a>] [<a href="https://doi.org/10.4049/jimmunol.167.11.6312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11714795">Khattri et al. (2001)</a> observed fewer T cells. These remaining T cells had poor proliferative and cytolytic responses and poor IL2 production, although thymic development appeared normal. Histologic analysis showed that peripheral lymphoid organs, particularly lymph nodes, were relatively acellular. <a href="#23" class="mim-tip-reference" title="Khattri, R., Kasprowicz, D., Cox, T., Mortrud, M., Appleby, M. W., Brunkow, M. E., Ziegler, S. F., Ramsdell, F. <strong>The amount of scurfin protein determines peripheral T cell number and responsiveness.</strong> J. Immun. 167: 6312-6320, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11714795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11714795</a>] [<a href="https://doi.org/10.4049/jimmunol.167.11.6312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11714795">Khattri et al. (2001)</a> concluded that excessive scurfin activity leads to a hypoactive immune state, suggesting that scurfin acts as a central regulator of T-cell activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11714795" 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 generating mice deficient in Foxp3, <a href="#15" class="mim-tip-reference" title="Fontenot, J. D., Gavin, M. A., Rudensky, A. Y. <strong>Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.</strong> Nature Immun. 4: 330-336, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612578</a>] [<a href="https://doi.org/10.1038/ni904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612578">Fontenot et al. (2003)</a> showed that Foxp3 is required for the development of CD4-positive/CD25-positive regulatory T cells. In addition, the IPEX-like lymphoproliferative autoimmune syndrome observed in Foxp3 -/- mice resulted from a deficiency in these regulatory T cells. The authors found that ectopic expression of Foxp3 activated a suppressor function in CD4-positive/CD25-negative T cells. Independently, <a href="#22" class="mim-tip-reference" title="Khattri, R., Cox, T., Yasayko, S.-A., Ramsdell, F. <strong>An essential role for Scurfin in CD4+CD25+ T regulatory cells.</strong> Nature Immun. 4: 337-342, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12612581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12612581</a>] [<a href="https://doi.org/10.1038/ni909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12612581">Khattri et al. (2003)</a> and <a href="#19" class="mim-tip-reference" title="Hori, S., Nomura, T., Sakaguchi, S. <strong>Control of regulatory T cell development by the transcription factor Foxp3.</strong> Science 299: 1057-1061, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522256</a>] [<a href="https://doi.org/10.1126/science.1079490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522256">Hori et al. (2003)</a> reached similar conclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12522256+12612578+12612581" 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="#50" class="mim-tip-reference" title="Wan, Y. Y., Flavell, R. A. <strong>Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression.</strong> Nature 445: 766-770, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220876</a>] [<a href="https://doi.org/10.1038/nature05479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220876">Wan and Flavell (2007)</a> noted that individuals with graft-versus-host disease, myasthenia gravis (see <a href="/entry/254200">254200</a>), and multiple sclerosis have decreased FOXP3 expression. They generated a mouse model in which endogenous Foxp3 expression was attenuated in Tr cells. These mice were born at a mendelian ratio. Heterozygous females were fertile and phenotypically normal, but hemizygous males were barren and runted. Most males developed scaly skin, and nearly all developed a blepharitis-like condition. All mutant males died by 3 months of age due to an aggressive lymphoproliferative autoimmune syndrome, including drastically increased serum autoantibodies; however, thymic development was not affected. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their in vitro anergy was maintained, including preferential development into Th2-type effector cells even in a Th1-polarizing environment. <a href="#50" class="mim-tip-reference" title="Wan, Y. Y., Flavell, R. A. <strong>Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression.</strong> Nature 445: 766-770, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220876/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220876</a>] [<a href="https://doi.org/10.1038/nature05479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220876">Wan and Flavell (2007)</a> concluded that decreased FOXP3 expression causes immune disease by subverting the suppressive function of Tr cells and converting Tr cells into effector cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220876" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V. C., Beavo, J. A., Rudensky, A. Y. <strong>Foxp3-dependent programme of regulatory T-cell differentiation.</strong> Nature 445: 771-775, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220874</a>] [<a href="https://doi.org/10.1038/nature05543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220874">Gavin et al. (2007)</a> studied mouse T cells that actively transcribed a Foxp3-null allele, but lacked Foxp3 protein. Using flow cytometric and microarray analyses, they found that, although Foxp3 function was required for Tr suppressor cell activity, Foxp3 largely amplified and fixed preexisting molecular features of Tr cells. Furthermore, Foxp3 solidified Tr-cell lineage stability by modifying cell surface and signaling molecules, including Foxp3-dependent repression of phosphodiesterase-3b (PDE3B; <a href="/entry/602047">602047</a>). Introduction of Pde3b into Tr cells and transfer of these cells to T-cell-deficient mice substantially reduced the number of Tr cells. <a href="#16" class="mim-tip-reference" title="Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V. C., Beavo, J. A., Rudensky, A. Y. <strong>Foxp3-dependent programme of regulatory T-cell differentiation.</strong> Nature 445: 771-775, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220874</a>] [<a href="https://doi.org/10.1038/nature05543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220874">Gavin et al. (2007)</a> proposed that reduced PDE3B expression may be a unique marker of Tr cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether dysfunction or a lack of Treg cells is etiologically involved in pathogenesis of mouse scurfy and its human correlate, IPEX, <a href="#24" class="mim-tip-reference" title="Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., Hamann, A., Wagner, H., Huehn, J., Sparwasser, T. <strong>Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.</strong> J. Exp. Med. 204: 57-63, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200412</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200412[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20061852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200412">Lahl et al. (2007)</a> generated BAC-transgenic mice termed 'depletion of regulatory T cell' (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent fusion protein under control of Foxp3. Injection of DT allowed selective and efficient detection and inducible depletion of Foxp3-positive Treg cells without affecting Cd25-positive effector T cells. Histopathologic analysis showed that DT injection in newborn DEREG mice ablated Treg cells and led to development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. <a href="#24" class="mim-tip-reference" title="Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., Hamann, A., Wagner, H., Huehn, J., Sparwasser, T. <strong>Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.</strong> J. Exp. Med. 204: 57-63, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200412</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200412[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20061852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200412">Lahl et al. (2007)</a> concluded that absence of Foxp3-positive Treg cells is sufficient to induce a scurfy-like phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200412" 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="Lund, J. M., Hsing, L., Pham, T. T., Rudensky, A. Y. <strong>Coordination of early protective immunity to viral infection by regulatory T cells.</strong> Science 320: 1220-1224, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18436744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18436744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18436744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1155209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18436744">Lund et al. (2008)</a> examined a role for regulatory T cells (Tregs) in mucosal herpes simplex virus infection using Foxp3 knockin mice harboring Treg subsets tagged with either green fluorescent protein (GFP) or human diphtheria toxin receptor. They observed an accelerated fatal infection with increase in viral load in the mucosa and central nervous system after ablation of Tregs. Although augmented interferon production was detected in the draining lymph nodes in Treg-deprived mice, it was profoundly reduced at the infection site. This was associated with a delay in the arrival of natural killer cells, dendritic cells, and T cells to the site of infection and a sharp increase in proinflammatory chemokine levels in the draining lymph nodes. <a href="#28" class="mim-tip-reference" title="Lund, J. M., Hsing, L., Pham, T. T., Rudensky, A. Y. <strong>Coordination of early protective immunity to viral infection by regulatory T cells.</strong> Science 320: 1220-1224, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18436744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18436744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18436744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1155209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18436744">Lund et al. (2008)</a> concluded that Tregs facilitate early protective responses to local viral infection by allowing a timely entry of immune cells into infected tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18436744" 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="#40" class="mim-tip-reference" title="Rowe, J. H., Ertelt, J. M., Aguilera, M. N., Farrar, M. A., Way, S. S. <strong>Foxp3+ regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens.</strong> Cell Host Microbe 10: 54-64, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21767812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21767812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21767812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.chom.2011.06.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21767812">Rowe et al. (2011)</a> showed that expansion of Foxp3-positive Tregs during pregnancy in mice conferred enhanced susceptibility to Listeria and Salmonella bacterial infection. Treg ablation reduced susceptibility, but it broke maternal tolerance to fetal antigen and triggered fetal resorption. However, mice with Foxp3-positive cells and defective Il10 had reduced infection susceptibility without affecting pregnancy outcome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21767812" 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="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> identified an arg397-to-trp mutation in the FOXP3 gene (due to 1189C-T) as the cause of IPEX (<a href="/entry/304790">304790</a>) in one of the patients previously reported by <a href="#26" class="mim-tip-reference" title="Levy-Lahad, E., Wildin, R. S. <strong>Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: further evidence for an X-linked lethal syndrome.</strong> J. Pediat. 138: 577-580, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11295725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11295725</a>] [<a href="https://doi.org/10.1067/mpd.2001.111502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11295725">Levy-Lahad and Wildin (2001)</a>. The infant died at age 5 weeks with insulin-dependent diabetes mellitus, enteropathy, hypothyroidism, thrombocytopenia, and peritonitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11295725+11137992" 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 infant with IPEX (<a href="/entry/304790">304790</a>) reported by <a href="#36" class="mim-tip-reference" title="Peake, J. E., McCrossin, R. B., Byrne, G., Shepard, R. <strong>X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea.</strong> Arch. Dis. Child. Fetal Neonatal Ed. 74: F195-F199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8777684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8777684</a>] [<a href="https://doi.org/10.1136/fn.74.3.f195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8777684">Peake et al. (1996)</a>, <a href="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> identified a deletion-insertion mutation (1290-1309del, TGG ins) in the FOXP3 gene. The infant died at age 10 months with IDDM, enteropathy, anemia, lymphadenopathy, eczema, and sepsis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8777684+11137992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122467169 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467169;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=rs122467169" 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=rs122467169" 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=RCV000012162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012162</a>
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<p>In a child with IPEX (<a href="/entry/304790">304790</a>), <a href="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> identified a phe371-to-cys mutation in the FOXP3 gene. The patient had IDDM, enteropathy, anemia, and exfoliated dermatitis, and was surviving after bone marrow transplant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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">rs122467170 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467170;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=rs122467170" 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=rs122467170" 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=RCV000012163" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012163" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012163</a>
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<p><a href="#51" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Dagna Bricarelli, F., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> identified an ala384-to-thr (A384T) mutation in the FOXP3 gene in an infant with IPEX (<a href="/entry/304790">304790</a>) who died at age 4 months with IDDM, enteropathy, hypothyroidism, thrombocytopenia, exfoliated dermatitis, and sepsis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large family with cases of IPEX in multiple sibships through 4 generations, previously reported by <a href="#13" class="mim-tip-reference" title="Ferguson, P. J., Blanton, S. H., Saulsbury, F. T., McDuffie, M. J., Lemahieu, V., Gastier, J. M., Francke, U., Borowitz, S. M., Sutphen, J. L., Kelly, T. E. <strong>Manifestations and linkage analysis in X-Linked autoimmunity-immunodeficiency syndrome.</strong> Am. J. Med. Genet. 90: 390-397, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10706361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10706361</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000228)90:5<390::aid-ajmg9>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10706361">Ferguson et al. (2000)</a>, <a href="#4" class="mim-tip-reference" title="Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D. <strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong> Nature Genet. 27: 20-21, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137993</a>] [<a href="https://doi.org/10.1038/83713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137993">Bennett et al. (2001)</a> identified an A384T mutation in the FOXP3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11137993+10706361" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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">rs1602679037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1602679037;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=rs1602679037" 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=rs1602679037" 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 of Japanese extraction, <a href="#4" class="mim-tip-reference" title="Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D. <strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong> Nature Genet. 27: 20-21, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137993</a>] [<a href="https://doi.org/10.1038/83713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137993">Bennett et al. (2001)</a> found that the single male with IPEX (<a href="/entry/304790">304790</a>) had a CT dinucleotide deletion at positions 1481-1482 within the FOXP3 termination codon, predicting a frameshift and addition of 25 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137993" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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">rs1426535368 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1426535368;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=rs1426535368" 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=rs1426535368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a kindred with IPEX (<a href="/entry/304790">304790</a>), <a href="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> found an A-to-G substitution at position +4 of the 5-prime donor splice junction of intron 9 of the FOXP3 gene. The substitution was not present in 2 sibs and the parents, including the mother, indicating that it arose de novo. Sequence analysis of RT-PCR-amplified JM2 mRNA transcripts revealed skipping of JM2 exon 9 in transcripts of the index case. Exon 9 skipping resulted in a frameshift at codon 273 that gave rise to a premature stop signal at codon 286. This led to the generation of a truncated JM2 protein that lacked the forkhead homology domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122467171 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467171;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=rs122467171" 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=rs122467171" 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=RCV000012166 OR RCV004566720" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012166, RCV004566720" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012166...</a>
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<p>In a kindred with IPEX (<a href="/entry/304790">304790</a>), <a href="#8" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> found that affected males were hemizygous for a deletion of 3 bp in exon 7 of the FOXP3 gene, resulting in loss of the glutamic acid-201 residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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">rs2147949186 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147949186;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=rs2147949186" 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=rs2147949186" 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=RCV000012167" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012167" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012167</a>
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<p>In the proband of a family with IPEX (<a href="/entry/304790">304790</a>), <a href="#34" class="mim-tip-reference" title="Owen, C. J., Jennings, C. E., Imrie, H., Lachaux, A., Bridges, N. A., Cheetham, T. D., Pearce, S. H. S. <strong>Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome.</strong> J. Clin. Endocr. Metab. 88: 6034-6039, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671208</a>] [<a href="https://doi.org/10.1210/jc.2003-031080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14671208">Owen et al. (2003)</a> identified a single-base deletion of adenine at the second position of codon 76 in exon 2 of the FOXP3 gene. The mutation resulted in frameshift leading to a truncated protein product (108 residues vs 431 in wildtype). The mother and the proband's 2 healthy sisters were carriers of the mutation. The brother of the proband had died at 6 weeks of age and was found to have a lymphoid cell infiltration of the pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671208" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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> rs122467172 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467172;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/rs122467172?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=rs122467172" 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=rs122467172" 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=RCV000012168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012168</a>
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<p>In a patient with severe IPEX (<a href="/entry/304790">304790</a>) who presented with IDDM at age 2 weeks, <a href="#2" class="mim-tip-reference" title="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a> identified a double substitution (TT to GC) at nucleotide 1305 in exon 10 of the FOXP3 gene, resulting in a phe373-to-ala (F373A) substitution in the forkhead domain. The mutation was present in the patient's mother, but not in a healthy brother who served as the source of an HLA-identical bone marrow transplant that resolved all IPEX symptoms except the IDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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>.0010 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</strong>
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FOXP3, PHE324LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122467173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467173;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=rs122467173" 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=rs122467173" 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=RCV000012169" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012169" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012169</a>
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<p><a href="#2" class="mim-tip-reference" title="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a> reported a patient with a mild form of IPEX (<a href="/entry/304790">304790</a>) who presented at age 4 months with severe enteritis and eczema and high serum IgE that resolved spontaneously. The patient had a T-to-C transition at nucleotide 970 in exon 9 of the FOXP3 gene, resulting in a phe324-to-leu (F324L) substitution in the forkhead domain, and a splice-site mutation, a C-to-T transition at nucleotide 543, affecting the 5-prime end of exon 5. The patient's healthy mother and an older brother who showed no symptoms of IPEX had the same mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</strong>
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FOXP3, 543C-T
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012170" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012170" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012170</a>
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<p>See <a href="#0010">300292.0010</a> and <a href="#2" class="mim-tip-reference" title="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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">rs122467174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467174;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=rs122467174" 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=rs122467174" 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=RCV000012171" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012171" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012171</a>
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<p>In a patient with severe IPEX (<a href="/entry/304790">304790</a>) who presented with neonatal IDDM, enteritis, recurrent skin infections, and hyper-IgE, <a href="#2" class="mim-tip-reference" title="Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G. <strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong> J. Clin. Invest. 116: 1713-1722, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI25112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16741580">Bacchetta et al. (2006)</a> identified a G-to-A transition in the first codon of the FOXP3 gene, resulting in a met1-to-ile (M1I) substitution and no protein expression. The mutation was not present in the patient's mother. An HLA-identical bone marrow transplant from an unrelated donor appeared to resolve symptoms of autoimmune disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</strong>
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FOXP3, PRO367LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122467175 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122467175;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=rs122467175" 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=rs122467175" 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=RCV000012172" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012172" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012172</a>
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<p>In a Japanese patient with IPEX (<a href="/entry/304790">304790</a>), <a href="#46" class="mim-tip-reference" title="Suzuki, S., Makita, Y., Mukai, T., Matsuo, K., Ueda, O., Fujieda, K. <strong>Molecular basis of neonatal diabetes in Japanese patients.</strong> J. Clin. Endocr. Metab. 92: 3979-3985, 2007. Note: Erratum: J. Clin. Endocr. Metab. 93: 153 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17635943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17635943</a>] [<a href="https://doi.org/10.1210/jc.2007-0486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17635943">Suzuki et al. (2007)</a> identified a pro367-to-leu (P367L) mutation in the FOX3P gene. The mutation occurred in the FKH domain, which is essential for DNA binding. The patient was born with severe SGA at 38 weeks' gestation. He presented with failure to thrive and was diagnosed with diabetes mellitus. He manifested intractable diarrhea and eczema, liver dysfunction with hyperammonemia, thrombocytopenia, and sepsis. At 14 weeks of age he suffered from acute renal failure resulting in congestive heart failure and pulmonary edema. He died at age 16 weeks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17635943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Allan2005" class="mim-anchor"></a>
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Allan, S. E., Passerini, L., Bacchetta, R., Crellin, N., Dai, M., Orban, P. C., Ziegler, S. F., Roncarolo, M. G., Levings, M. K.
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<strong>The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs.</strong>
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J. Clin. Invest. 115: 3276-3284, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16211090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16211090</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16211090[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16211090" 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/10.1172/JCI24685" target="_blank">Full Text</a>]
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Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G.
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<strong>Defective regulatory and effector T cell functions in patients with FOXP3 mutations.</strong>
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J. Clin. Invest. 116: 1713-1722, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16741580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16741580</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16741580[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16741580" 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/10.1172/JCI25112" target="_blank">Full Text</a>]
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Bassuny, W. M., Ihara, K., Sasaki, Y., Kuromaru, R., Kohno, H., Matsuura, N., Hara, T.
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<strong>A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes.</strong>
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Immunogenetics 55: 149-156, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750858" 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/s00251-003-0559-8" target="_blank">Full Text</a>]
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Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D.
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<strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong>
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Nature Genet. 27: 20-21, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137993</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137993" 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/10.1038/83713" target="_blank">Full Text</a>]
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Bettelli, E., Dastrange, M., Oukka, M.
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<strong>Foxp3 interacts with nuclear factor of activated T cells and NF-kappa-B to repress cytokine gene expression and effector functions of T helper cells.</strong>
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Proc. Nat. Acad. Sci. 102: 5138-5143, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790681</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15790681[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15790681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0501675102" target="_blank">Full Text</a>]
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<a id="Brunkow2001" class="mim-anchor"></a>
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Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F.
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<strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong>
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Nature Genet. 27: 68-73, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11138001" 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/10.1038/83784" target="_blank">Full Text</a>]
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<a id="Casetti2009" class="mim-anchor"></a>
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Casetti, R., Agrati, C., Wallace, M., Sacchi, A., Martini, F., Martino, A., Rinaldi, A., Malkovsky, M.
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<strong>Cutting edge: TGF-beta-1 and IL-15 induce FOXP3(+) gamma-delta regulatory T cells in the presence of antigen stimulation.</strong>
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J. Immun. 183: 3574-3577, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19710458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19710458</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19710458" 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/10.4049/jimmunol.0901334" target="_blank">Full Text</a>]
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<a id="Chatila2000" class="mim-anchor"></a>
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Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M.
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<strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong>
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J. Clin. Invest. 106: R75-R81, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" 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/10.1172/JCI11679" target="_blank">Full Text</a>]
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<a id="Clark1999" class="mim-anchor"></a>
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Clark, L. B., Appleby, M. W., Brunkow, M. E., Wilkinson, J. E., Ziegler, S. F., Ramsdell, F.
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<strong>Cellular and molecular characterization of the scurfy mouse mutant.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072494</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10072494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Cortez2020" class="mim-anchor"></a>
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Cortez, J. T., Montauti, E., Shifrut, E., Gatchalian, J., Zhang, Y., Shaked, O., Xu, Y., Roth, T. L., Simeonov, D. R., Zhang, Y., Chen, S., Li, Z., and 13 others.
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<strong>CRISPR screen in regulatory T cells reveals modulators of Foxp3.</strong>
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Nature 582: 416-420, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32499641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32499641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32499641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32499641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-020-2246-4" target="_blank">Full Text</a>]
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<a id="Dang2011" class="mim-anchor"></a>
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Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., Pan, F.
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<strong>Control of TH17/T-reg balance by hypoxia-inducible factor 1.</strong>
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Cell 146: 772-784, 2011.
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1016/j.immuni.2013.01.013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20131142" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17570480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17570480</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17570480[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17570480" 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.2007.04.034" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Bao Lige - updated : 07/22/2024
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/22/2021<br>Ada Hamosh - updated : 10/28/2020<br>Ada Hamosh - updated : 09/23/2020<br>Ada Hamosh - updated : 12/12/2016<br>Paul J. Converse - updated : 06/12/2014<br>Paul J. Converse - updated : 2/11/2014<br>Paul J. Converse - updated : 9/13/2013<br>Ada Hamosh - updated : 10/24/2012<br>Patricia A. Hartz - updated : 9/21/2012<br>Paul J. Converse - updated : 3/15/2012<br>Ada Hamosh - updated : 5/19/2011<br>Paul J. Converse - updated : 1/7/2011<br>Ada Hamosh - updated : 12/28/2010<br>Paul J. Converse - updated : 10/26/2010<br>Paul J. Converse - updated : 9/14/2010<br>Paul J. Converse - updated : 8/3/2010<br>Ada Hamosh - updated : 3/5/2010<br>Matthew B. Gross - updated : 10/27/2009<br>Paul J. Converse - updated : 10/20/2009<br>Ada Hamosh - updated : 9/15/2009<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Ada Hamosh - updated : 4/7/2009<br>Ada Hamosh - updated : 4/2/2009<br>Ada Hamosh - updated : 7/21/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>John A. Phillips, III - updated : 5/22/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Paul J. Converse - updated : 8/7/2007<br>Ada Hamosh - updated : 6/29/2007<br>Paul J. Converse - updated : 5/22/2007<br>Ada Hamosh - updated : 4/27/2007<br>Ada Hamosh - updated : 4/20/2007<br>Paul J. Converse - updated : 3/14/2007<br>Paul J. Converse - updated : 2/15/2007<br>Paul J. Converse - updated : 7/20/2006<br>Paul J. Converse - updated : 2/13/2006<br>Paul J. Converse - updated : 11/9/2005<br>Paul J. Converse - updated : 6/23/2005<br>John A. Phillips, III - updated : 4/1/2005<br>Natalie E. Krasikov - updated : 2/10/2004<br>Victor A. McKusick - updated : 9/22/2003<br>Paul J. Converse - updated : 3/26/2003<br>Paul J. Converse - updated : 2/26/2003<br>Paul J. Converse - updated : 2/15/2002<br>Victor A. McKusick - updated : 12/5/2001
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/2/2001
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mgross : 07/22/2024
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alopez : 09/22/2021<br>mgross : 12/08/2020<br>mgross : 10/28/2020<br>alopez : 09/23/2020<br>carol : 10/02/2019<br>carol : 10/01/2019<br>carol : 01/27/2017<br>alopez : 12/12/2016<br>alopez : 10/14/2016<br>mgross : 06/12/2014<br>mgross : 6/11/2014<br>mcolton : 5/29/2014<br>mgross : 2/11/2014<br>mcolton : 1/17/2014<br>mcolton : 1/17/2014<br>mgross : 9/13/2013<br>mgross : 9/13/2013<br>mgross : 9/13/2013<br>terry : 3/28/2013<br>terry : 3/15/2013<br>mgross : 2/5/2013<br>alopez : 10/26/2012<br>terry : 10/24/2012<br>mgross : 9/26/2012<br>terry : 9/21/2012<br>terry : 6/7/2012<br>mgross : 3/20/2012<br>terry : 3/16/2012<br>terry : 3/15/2012<br>terry : 3/15/2012<br>mgross : 12/16/2011<br>alopez : 5/19/2011<br>mgross : 2/4/2011<br>terry : 1/7/2011<br>alopez : 1/4/2011<br>terry : 12/28/2010<br>mgross : 11/4/2010<br>terry : 11/3/2010<br>terry : 10/29/2010<br>mgross : 10/28/2010<br>terry : 10/26/2010<br>mgross : 9/14/2010<br>alopez : 8/6/2010<br>terry : 8/3/2010<br>alopez : 3/8/2010<br>alopez : 3/8/2010<br>terry : 3/5/2010<br>mgross : 10/27/2009<br>terry : 10/20/2009<br>alopez : 9/15/2009<br>terry : 9/15/2009<br>wwang : 9/14/2009<br>terry : 9/10/2009<br>alopez : 4/8/2009<br>terry : 4/7/2009<br>alopez : 4/3/2009<br>alopez : 4/3/2009<br>terry : 4/2/2009<br>mgross : 11/10/2008<br>terry : 11/7/2008<br>alopez : 7/21/2008<br>mgross : 6/17/2008<br>terry : 5/28/2008<br>carol : 5/22/2008<br>mgross : 8/30/2007<br>terry : 8/23/2007<br>mgross : 8/23/2007<br>terry : 8/7/2007<br>alopez : 7/3/2007<br>terry : 6/29/2007<br>mgross : 5/22/2007<br>alopez : 5/11/2007<br>alopez : 5/11/2007<br>terry : 4/27/2007<br>alopez : 4/24/2007<br>terry : 4/20/2007<br>mgross : 3/14/2007<br>mgross : 3/14/2007<br>terry : 3/14/2007<br>terry : 3/14/2007<br>mgross : 2/15/2007<br>mgross : 2/15/2007<br>mgross : 8/3/2006<br>mgross : 8/3/2006<br>terry : 7/20/2006<br>mgross : 2/13/2006<br>mgross : 11/9/2005<br>mgross : 6/23/2005<br>alopez : 4/1/2005<br>carol : 2/10/2004<br>carol : 9/25/2003<br>tkritzer : 9/23/2003<br>tkritzer : 9/22/2003<br>alopez : 4/1/2003<br>mgross : 3/26/2003<br>mgross : 3/26/2003<br>mgross : 2/26/2003<br>carol : 9/18/2002<br>mgross : 2/15/2002<br>alopez : 12/13/2001<br>alopez : 12/7/2001<br>terry : 12/5/2001<br>carol : 7/3/2001<br>carol : 1/3/2001<br>carol : 1/3/2001<br>carol : 1/3/2001<br>carol : 1/2/2001
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<span class="mim-font">
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<strong>*</strong> 300292
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<h3>
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<span class="mim-font">
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FORKHEAD BOX P3; FOXP3
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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SCURFIN<br />
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JM2
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<strong><em>HGNC Approved Gene Symbol: FOXP3</em></strong>
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<strong>SNOMEDCT:</strong> 724276006;
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<strong>
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Cytogenetic location: Xp11.23
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Genomic coordinates <span class="small">(GRCh38)</span> : X:49,250,438-49,264,710 </span>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<span class="mim-font">
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Xp11.23
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<td>
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<span class="mim-font">
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Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
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</td>
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<td>
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<span class="mim-font">
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304790
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<span class="mim-font">
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X-linked recessive
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-font">
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>FOXP3, a member of the fork-winged helix family of transcription factors, plays an important role in the development and function of naturally occurring CD4 (186940)-positive/CD25 (IL2RA; 147730)-positive T regulatory cells (Tregs). Tregs are involved in active suppression of inappropriate immune responses (summary by Ricciardelli et al., 2008). </p>
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<div>
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<br />
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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 class="mim-text-font">
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<p>By combining high-resolution genetic and physical mapping with large-scale sequence analysis, Brunkow et al. (2001) identified the gene defective in 'scurfy' (sf) mice (see ANIMAL MODEL). The protein encoded by this gene, designated Foxp3, is a member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. </p><p>Brunkow et al. (2001) compared the amino acid sequences of mouse and human scurfin with other members of the forkhead/winged-helix/HNF3 family of proteins and found the strongest similarity to the sequence of glutamine-rich factor-1 (FOXP1; 605515). </p><p>Chatila et al. (2000) stated that the human FOXP3 open reading frame of 1,146 bp encodes a deduced 381-amino acid protein. By PCR of a human peripheral blood mononuclear cell cDNA library, Smith et al. (2006) cloned full-length FOXP3 and splice variants lacking exon 2 and both exons 2 and 7. The full-length protein contains 431 amino acids. The variant lacking exon 2 encodes a 396-amino acid protein lacking part of the proline-rich domain, and the variant lacking exons 2 and 7 encodes a 369-amino acid protein that also lacks a large part of the putative leucine zipper. Smith et al. (2006) noted that mice appear to lack Foxp3 variants. </p>
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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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</div>
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<span class="mim-text-font">
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<p>Brunkow et al. (2001) determined that the mouse and human FOXP3 genes contain 11 coding exons. Exon-intron boundaries are identical across the coding regions of the mouse and human genes. </p>
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</span>
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<div>
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<br />
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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, Chatila et al. (2000) mapped the FOXP3 gene to chromosome Xp11.23. </p>
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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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</div>
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<span class="mim-text-font">
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<p>Due to similarities between the autoimmunity and inflammation produced by manipulation of CD25-positive/CD4-positive regulatory T (Tr, or Treg) cells and those induced by genetic defects in the FOXP3 gene, Hori et al. (2003) investigated the contribution of Foxp3 to the development and/or function of Tr cells in mice. RT-PCR analysis of normal mice showed stable, constitutive expression of Foxp3 that was high in Tr cells, low in CD4-positive/CD25-negative cells, and absent in CD4-negative/CD8 (see CD8A; 186910)-positive T cells. Transduced expression of Foxp3 in CD4-positive/CD25-negative cells imparted a Tr phenotype in these cells, with low levels of cytokine expression, compared with nontransduced or vector-only transduced cells, and high levels of CD103 (604682), GITR (TNFRSF18; 603905), and CTLA4 (123890). Transduced cells also showed cell-cell contact suppressive activity in vitro, as well as suppression of autoimmunity and inflammation in vivo. Hori et al. (2003) proposed that FOXP3 may be a master regulatory gene and a more specific marker of Tr cells than other cell surface molecules. They also suggested that FOXP3 transduction could be a therapeutic mode for the treatment of inflammatory diseases. </p><p>Stock et al. (2004) described a type of antigen-specific Tr cell that developed in vivo from naive CD4-positive/CD25-negative T cells during a Th1 polarized immune response. These Tr cells were induced by CD8A-positive dendritic cells, produced both IFNG (147570) and IL10 (124092), and expressed the Th1 'master transcription factor' TBET (TBX21; 604895), as well as ICOS (604558) and FOXP3. The cells inhibited allergen-induced airway hyperreactivity in an IL10-dependent manner in mice. Stock et al. (2004) concluded that these adaptive Tr cells are related to, but distinct from, Th1 cells. They proposed that a spectrum of adaptive Tr cell types exists, comprising Th1-like cells and the previously reported Th2-like cells that are induced by CD8A-negative dendritic cells and express the Th2 'master transcription factor' GATA3 (131320) and FOXP3. </p><p>Using a bicistronic reporter expressing red fluorescent protein knocked in to the endogenous mouse Foxp3 locus, Wan and Flavell (2005) demonstrated that Foxp3 was expressed predominantly in CD4-positive/CD25-positive T cells, but also in some other CD4-positive T-cell subsets. Stimulation of activated CD4 T cells with TGFB induced both Foxp3 expression and suppressor T-cell function. </p><p>FOXP1, FOXP2 (605317), and FOXP3 all bind the FOX-binding site within the IL2 (147680) promoter, and all but FOXP2 suppress IL2 promoter activity. However, Bettelli et al. (2005) found that forced expression of FOXP3, but not FOXP1 or FOXP2, in naive T cells suppressed not only IL2, but also IL4 (147780) and IFNG due to its ability to physically associate with and inhibit the cytokine gene transactivators NFKB (see 164011) and NFAT (see 600490). T cells derived from Foxp3-deficient scurfy mice had significantly increased Nfat and Nfkb expression, which could be lowered to physiologic levels by FOXP3 gene complementation. Transduction of myelin proteolipid protein (PLP1; 300401)-specific autoreactive mouse T cells with FOXP3 eliminated their ability to mediate experimental autoimmune encephalomyelitis. Bettelli et al. (2005) concluded that, in addition to being associated with generation of CD4-positive/CD25-positive regulatory T cells, FOXP3 acts on mature T cells by repressing NFAT and NFKB. </p><p>Allan et al. (2005) found that, in contrast with results in mouse, overexpression of human FOXP3 alone or together with a splice variant lacking exon 2 in CD4-positive/CD25-positive regulatory T cells resulted in lower proliferation and IL2 production, but no increase in suppressive activity. Allan et al. (2005) suggested that factors in addition to FOXP3 are required for development of regulatory T cells. </p><p>Copolymer I (COP-I) is a random polymer of 4 amino acids (glu, lys, ala, and tyr) enriched in myelin basic protein (MBP; 159430) that is used to treat multiple sclerosis (MS; see 126200). Hong et al. (2005) found that COP-I increased expression of FOXP3 in peripheral blood CD4-positive T cells of MS patients and induced conversion of CD4-positive/CD25-negative cells to CD4-positive/CD25-positive regulatory T cells. Induction of FOXP3 in CD4-positive T cells was mediated by IFNG. Mice lacking Ifng exhibited an increase in Cd4-positive/Cd25-positive cells after COP-I treatment, but these cells did not express Foxp3. Hong et al. (2005) concluded that COP-I-mediated activation of FOXP3 expression and conversion of CD4-positive/CD25-negative cells to CD4-positive/CD25-positive regulatory T cells requires IFNG. </p><p>Smith et al. (2006) found that overexpression of full-length FOXP3 or of the FOXP3 variants lacking exon 2 or both exons 2 and 7 reduced CD4-positive T-cell proliferation and cytokine secretion. </p><p>Pennington et al. (2006) showed that without any obvious effect on T cell receptor-mediated selection, the normal differentiation of mouse gamma-delta T cells into potent cytolytic and interferon-gamma-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+/CD8+ T cell progenitors to influence in trans early gamma-delta cell progenitors. Unexpectedly, Pennington et al. (2006) found that the propensity of early T cell receptor alpha-beta(+) progenitors to differentiate into Foxp3+ regulatory T cells is also regulated in trans by CD4+/CD8+ T-cell progenitor cells, before agonist selection. </p><p>Ono et al. (2007) demonstrated that the transcription factor AML1/RUNX1 (151385), which is crucially required for normal hematopoiesis including thymic T cell development, activates IL2 and IFN-gamma gene expression in conventional CD4+ T cells through binding to their respective promoters. In natural Treg cells, FOXP3 interacts physically with AML1. Several lines of evidence supported a model in which the interaction suppresses IL2 and IFN-gamma production, upregulates Treg cell-associated molecules, and exerts suppressive activity. Ono et al. (2007) concluded that this transcriptional control of Treg cell function by an interaction between FOXP3 and AML1 can be exploited to control physiologic and pathologic T cell-mediated immune responses. </p><p>Marson et al. (2007) identified FOXP3 target genes and reported that many of these are key modulators of T cell activation and function. Remarkably, the predominant, although not exclusive, effect of FOXP3 occupancy is to suppress the activation of target genes on T cell stimulation. FOXP3 suppression of its targets appears to be crucial for the normal function of regulatory T cells, because overactive variants of some target genes are known to be associated with autoimmune disease. </p><p>Zheng et al. (2007) used genomewide analysis combining chromatin immunoprecipitation with mouse genome tiling array profiling to identify Foxp3 binding regions for approximately 700 genes and for an intergenically encoded microRNA. The authors found that a large number of Foxp3-bound genes are up- or downregulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcriptional activator and repressor. Foxp3-mediated regulation unique to the thymus affects, among others, genes encoding nuclear factors that control gene expression and chromatin remodeling. In contrast, Foxp3 target genes shared by the thymic and peripheral regulatory T cells encode primarily plasma membrane proteins, as well as cell signaling proteins. Zheng et al. (2007) concluded that distinct transcriptional subprograms implemented by Foxp3 establish regulatory T cell lineage during differentiation and its proliferative and functional competence in the periphery. </p><p>Zuo et al. (2007) observed that female mice heterozygous for the scurfin mutation developed cancer at a high rate. The majority of cancers were mammary carcinomas in which the wildtype Foxp3 allele was inactivated and Erbb2 (164870) was overexpressed. Zuo et al. (2007) found that Foxp3 repressed transcription of the Erbb2 gene via interaction with forkhead DNA-binding motifs in the Erbb2 promoter. FOXP3 expression was reduced in 10 human tumor cell lines compared with normal mammary epithelial cells and a nonmalignant cell line, and none of the tumor cell lines expressed full-length FOXP3 transcripts. </p><p>Zuo et al. (2007) found that mouse mammary carcinomas heterozygous for a Foxp3 mutation exhibited increased Skp2 (601436) expression. Downregulation of FOXP3 by small interfering RNA in human mammary epithelial cells led to increased SKP2 expression. Reporter gene assays revealed that mouse Foxp3 directly interacted with and repressed the Skp2 promoter. Analysis of more than 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Zuo et al. (2007) concluded that FOXP3 is an SKP2 transcriptional repressor. </p><p>Using immunohistochemistry, immunofluorescence microscopy, and RT-PCR, Ricciardelli et al. (2008) showed that children with Crohn disease (266600) treated with infliximab, an anti-TNF (191160) antibody, had increased FOXP3-positive Tregs in their mucosa after treatment. Before treatment, FOXP3-positive T cells were reduced compared with controls. Ricciardelli et al. (2008) concluded that infliximab not only neutralizes soluble TNF, but also affects the activation and possibly the expansion of mucosal Tregs. </p><p>Zheng et al. (2009) showed that in mouse T regulatory cells, high amounts of interferon regulatory factor-4 (IRF4; 601900), a transcription factor essential for TH2 effector cell differentiation, is dependent on Foxp3 expression. They proposed that IRF4 expression endows T regulatory cells with the ability to suppress TH2 responses. Indeed, ablation of a conditional Irf4 allele in T regulatory cells resulted in selective dysregulation of TH2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear cell-dominated pathology typical of mice lacking T regulatory cells. Zheng et al. (2009) concluded that T regulatory cells use components of the transcriptional machinery, promoting a particular type of effector CD4+ T cell differentiation, to efficiently restrain the corresponding type of the immune response. </p><p>Tsuji et al. (2009) demonstrated that suppressive Foxp3+CD4+ T cells can differentiate into follicular B helper T cells (T-FH) in mouse Peyer patches. The conversion of Foxp3+ T cells into T-FH cells requires the loss of Foxp3 expression and subsequent interaction with B cells. Thus, Tsuji et al. (2009) concluded that environmental cues present in gut Peyer patches promote the selective differentiation of distinct helper T cell subsets, such as T-FH cells. </p><p>Feuerer et al. (2009) examined Treg cells in mouse abdominal adipose tissue and found that more than half of the CD4(+) T cells expressed Foxp3, a much higher fraction than normally seen even in subcutaneous fat; and there was progressive accumulation of CD4(+)/Foxp3(+) Treg cells over time in the visceral, but not the subcutaneous, depot. Comparison of the documented Treg cell signature with that of Treg cells from abdominal fat revealed that many of the signature Treg cell genes were not significantly up- or downregulated in the corresponding population from visceral fat. This unique population of Treg cells was specifically reduced in abdominal fat in insulin-resistant mouse models of obesity, and loss- and gain-of-function experiments revealed that these Treg cells influenced the inflammatory state of adipose tissue and, therefore, insulin resistance. Cytokines differentially synthesized by fat-resident Treg and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. Analysis of paired frozen omental and subcutaneous fat tissues from individuals with body mass indices (BMIs) in the obese to morbidly obese range showed a correlation between BMI and the drop in Treg cells in omental versus subcutaneous fat. Feuerer et al. (2009) concluded that CD4(+)/FOXP3(+) Treg cells play a role in metabolic homeostasis and in its dysregulation in obesity. </p><p>Pan et al. (2009) identified Eos (606239), a zinc finger transcription factor of the Ikaros family, as a critical mediator of FOXP3-dependent gene silencing in Tregs. Eos interacted directly with FOXP3 and induced chromatin modifications that resulted in gene silencing in Tregs. Pan et al. (2009) found that silencing of Eos in Tregs abrogated their ability to suppress immune responses and endowed them with partial effector function, thus demonstrating the critical role that Eos plays in Treg programming. </p><p>FOXP3-positive Treg cells occasionally lose their suppressive phenotype to perform a helper-like role without losing expression of FOXP3. Sharma et al. (2013) showed that reprogramming of mouse Treg cells was controlled by Il6 (147620)-dependent downregulation of Eos. Treatment of Foxp3-positive Treg cells with cycloheximide showed that most retained Eos expression (i.e., they were Eos-stable), whereas a Cd38 (107270)-positive subset rapidly lost Eos expression (i.e., they were Eos-labile) with no change in Foxp3 expression. Thymic Treg cells from Il6 -/- mice did not express Cd38 and did not have an Eos-labile subset. Successful vaccination of naive mice required the Cd38-positive/Eos-labile subset of Treg cells. However, immunodeficient mice were fully protected from colitis by both Eos-stable and Eos-labile Treg cells. Epigenetic analysis of spleen and thymus Treg cells revealed significant differences in methylation between Eos-labile and Eos-stable cells. Eos downregulation was prevented by tumor-induced Ido (147435). Sharma et al. (2013) concluded that the Eos corepressor defines 2 sets of FOXP3-positive Treg cells, one that is stably suppressive and the other a labile one that is available in certain circumstances to provide helper activity. </p><p>Using flow cytometric analysis, Casetti et al. (2009) demonstrated that, like alpha-beta T cells, gamma-delta cells can also function as Tregs that express FOXP3 when stimulated with phosphoantigen in the presence of TGFB1 (190180) and IL15 (600554). </p><p>Zheng et al. (2010) described the function of 3 Foxp3 conserved noncoding DNA sequence (CNS) elements termed CNS1-3 in T regulatory cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T regulatory cells generated in the thymus and the periphery, binds c-Rel (164910) in in vitro assays. In contrast, CNS1, which contains a TGF-beta (190180)-NFAT (see 600489) response element, is superfluous for thymic T regulatory cell differentiation, but has a prominent role in periphery T regulatory cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T regulatory cells. Foxp3 binds to CNS2 in a Cbf-beta (121360)-Runx1 (151385) and CpG DNA demethylation-dependent manner, suggesting that FOXP3 recruitment to this cellular memory module facilitates the heritable maintenance of the active state of the FOXP3 locus and, therefore, T regulatory lineage stability. Zheng et al. (2010) concluded that their studies demonstrated that the composition, size, and maintenance of the T regulatory cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues. </p><p>Human T-lymphotropic virus (HTLV)-1 is a persistent retrovirus estimated to infect 10 to 20 million people. The majority of infected individuals are asymptomatic carriers, but 1 to 3% of infected individuals develop progressive inflammation of the central nervous system (see 159580), and about 4% of seropositive individuals develop a malignant lymphoproliferative disorder called adult T-cell leukemia/lymphoma (ATLL). Toulza et al. (2010) found that there was a high concentration of plasma CCL22 (602957) in HTLV-1-infected individuals and that the concentration was strongly correlated with the frequency of FOXP3-positive cells, which express the CCL22 receptor CCR4 (604836). CCL22 was produced by cells that expressed the HTLV-1 transactivator protein Tax, and the increased CCL22 enhanced the migration and survival of FOXP3-positive cells in vitro. Toulza et al. (2010) concluded that HTLV-1-induced CCL22 causes the high frequency of FOXP3-positive cells observed in HTLV-1 infection and that FOXP3-positive cells may both retard the progression of ATLL and HTLV-1-associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection. </p><p>Using RT-PCR and flow cytometric analysis, Miura et al. (2004) showed that the cytokine storm associated with graft-versus-host disease (GVHD; see 614395) correlated with decreased FOXP3 expression in mononuclear cells of bone marrow transplant patients. FOXP3 expression was higher in patients without GVHD. FOXP3 expression positively correlated with the presence of recent thymic emigrants. Miura et al. (2004) suggested that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms after transplantation, and that decreased regulatory mechanisms provide an environment that permits development of GVHD. </p><p>Using flow cytometric analysis to identify Treg frequencies in 32 blood donors with acute West Nile virus (WNV; see 610379) infection, Lanteri et al. (2009) demonstrated that CD4-positive/FOXP3-positive Treg frequencies increased in all individuals in the 3 months after the index donation that revealed WNV RNA in plasma. However, symptomatic donors exhibited lower Treg frequencies up to 1 year after index donation without showing systemic T-cell or generalized inflammatory responses. Studies in WNV-infected mice showed that symptomatic mice displayed lower Treg frequencies than asymptomatic mice. Moreover, mice lacking Foxp3-positive Tregs experienced increased lethality following WNV infection compared with controls. Lanteri et al. (2009) concluded that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans. </p><p>Liu et al. (2010) reported that the SUMO E3 ligase PIAS1 (603566) restricts the differentiation of natural T regulatory cells by maintaining a repressive chromatin state of the FOXP3 promoter. PIAS1 acts by binding to the FOXP3 promoter to recruit DNA methyltransferases and heterochromatin protein-1 (CBX5; 604478) for epigenetic modifications. PIAS1 deletion caused promoter demethylation, reduced histone H3 methylation (see 602810) at lys9, and enhanced promoter accessibility. Consistently, Pias1-null mice displayed an increased natural T regulatory cell population and were resistant to the development of experimental autoimmune encephalomyelitis. Liu et al. (2010) concluded that their studies identified an epigenetic mechanism that negatively regulates the differentiation of natural T regulatory cells. </p><p>Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argued instead for the developmentally ordered appearance (or 'layering') of distinct HSCs that give rise to distinct lymphocyte lineages at different stages of development. Mold et al. (2010) provided evidence of an analogous layered immune system in humans. Mold et al. (2010) investigated whether fetal and adult HSPCs might differ in their capacity to generate Tregs in the thymus, because fetal T cells appear to be predisposed to generating Foxp3+ Tregs upon stimulation in vitro, and there is an abundance of Tregs in the peripheral tissues of midgestation fetuses. Both fetal liver- and fetal bone marrow-derived HSPCs were found to generate populations of CD25+Foxp3+ SP4 thymocytes. Thus it appeared that fetal HSPCs display a heightened capacity to generate Tregs during thymic maturation. Mold et al. (2010) provided evidence that the fetal T cell lineage is biased toward immune tolerance. They concluded that their observations offered a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth. </p><p>Using predominantly wildtype and Hif1a (603348)-/- mouse T cells, Dang et al. (2011) showed that Hif1a was specifically required for differentiation of naive T cells into interleukin-17 (IL17; 603149)-expressing helper T (Th) cells. Hif1a interacted directly with Ror-gamma-t (RORC; 602943) and acetyltransferase p300 (EP300; 602700) at the Il17 promoter, and all 3 factors were required for optimum Il17 expression. Simultaneously, Hif1a downregulated differentiation of naive T cells into Treg cells by directing proteasomal degradation of Foxp3 by a mechanism that was independent of Hif1a transcriptional activity. Differentiation of Th17 cells and loss of Treg cells was enhanced in cultures subjected to hypoxic conditions. Knockout of Hif1a in mouse T cells rendered mice highly resistant to Mog (159465)-induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Dang et al. (2011) concluded that HIF1A has a role in immune responses by controlling the balance between Th17 and Treg cells. </p><p>Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3+ regulatory T cells (Treg cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. Rowe et al. (2012) showed that pregnancy selectively stimulates the accumulation of maternal FOXP3+ CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific Treg cells persist at elevated levels, maintain tolerance to preexisting fetal antigen, and rapidly reaccumulate during subsequent pregnancy. The accelerated expansion of Treg cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3+ cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of preexisting FOXP3+ cells each contribute to Treg expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3+ cell ablation. Thus, Rowe et al. (2012) concluded that pregnancy imprints FOXP3+ CD4 cells that sustain protective regulatory memory to fetal antigen. </p><p>By yeast 2-hybrid and coimmunoprecipitation analyses, Huang et al. (2013) showed that the proline-rich N terminus of FOXP3 interacted with the C terminus of FIK, an isoform of ZFP90 (609451). They noted that this region of FOXP3 also interacts with IKZF4 and KAT5 (601409), suggesting that it is involved in regulating repressive chromatin-remodeling complexes. Expression of FOXP3 and FIK in Jurkat T cells led to decreased expression of IL2 and IFNG, and chromatin immunoprecipitation analysis showed that FOXP3, FIK, and KAP1, which binds to the A box within the KRAB domain of FIK, were present on the same site on the IL2 and IFNG promoters. FIK was highly expressed in Tregs, and disruption of the FOXP3-FIK-KAP1 complex in Tregs abrogated their suppressor activity. Huang et al. (2013) concluded that FIK has a critical role in regulating FOXP3 activity and Treg function. </p><p>Smigiel et al. (2014) noted that FOXP3-positive Tregs depend on IL2 (147680) for maintaining tolerance and preventing autoimmunity. They showed that mouse central Tregs (cTregs), which express low levels of Cd44 (107269) and high levels of Cd62l (SELL; 153240) (i.e., Cd44-lo/Cd62l-hi), were quiescent and long-lived. In contrast, mouse effector Tregs (eTregs), which are Cd44-hi/Cd62l-lo, differentiated from cTregs and underwent rapid proliferation that was balanced by a high rate of apoptotic cell death. Although eTregs expressed lower levels of Cd25, they responded well to Il2. cTregs gained access to paracrine Il2 through their expression of Ccr7 (600242), whereas eTregs populating nonlymphoid tissues expressed low Ccr7, did not access Il2-prevalent regions in vivo, and were insensitive to Il2 blockade. eTregs were maintained by signaling through Icos. Smigiel et al. (2014) concluded that there is a fundamental homeostatic subdivision in Treg populations based on their localization and signaling mechanisms in different environments. </p><p>In mice, Feng et al. (2015) explored whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. Feng et al. (2015) showed that the intronic Foxp3 enhancer conserved noncoding sequence-3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. </p><p>Hang et al. (2019) screened a library of bile acid metabolites and identified 2 distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of Th17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-gamma-t (ROR-gamma-t; 602943) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS)3; this represented a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced Th17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Hang et al. (2019) concluded that their data suggested mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of Th17 and Treg cells. </p><p>Using a CRISPR-based loss-of-function screen in mouse regulatory T cells (Tregs), Cortez et al. (2020) identified several modulators of Foxp3 expression, including the deubiquitinase Usp22 (612116) as a positive regulator of Foxp3, and the E3 ubiquitin ligase Rnf20 (607699) as a negative regulator. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in Treg suppressive function, resulting in spontaneous autoimmunity and protection against tumor growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Tregs could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Tregs. </p><p>Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The regression and eventual termination of GCs are factors that ultimately limit the extent to which antibodies mature within a single reaction. Jacobsen et al. (2021) demonstrated that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to upregulation of the transcription factor Foxp3 by T follicular helper (TFH) cells. Ectopic expression of Foxp3 in TFH cells is sufficient to decrease GC size, implicating the natural upregulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes. </p>
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<p>Using pull-down assays, Zhang et al. (2023) demonstrated that purified recombinant mouse Foxp3 bound genomic DNA containing T(n)G (where n = 2 through 5) repeat-like sequences. T(n)G repeat-like elements were important for the interaction, and Foxp3 bound only a small fraction of T(n)G repeat-like sequences in accessible functional sites for transcriptional regulation, despite the widespread presence of T(n)G repeat-like sequences in the mouse genome. Foxp3 multimerized on T(n)G repeats. The cryoelectron microscopy structure of Foxp3 in a complex with a T(3)G 18-mer repeat revealed a ladder-like architecture, whereby 2 double-stranded DNA molecules formed the 2 'side rails,' bridged by 5 pairs of Foxp3 molecules, with each pair forming a 'rung' through interaction between 2 Foxp3 protein molecules (intra-rung interactions). Each Foxp3 subunit occupied TGTTTGT within the repeats in a manner that was indistinguishable from that of Foxp3 bound to the forkhead consensus motif (TGTTTAC). DNA bridging between T(n)G repeats was present in solution, and Foxp3 multimerization on T(n)G repeats contributed to long-distance chromatin contacts in Treg cells. Mutations in the intra-rung interface impaired T(n)G repeat recognition, DNA bridging, and Foxp3 cellular functions, without affecting binding to the forkhead consensus motif. The rungs were separated by 8 bp or 12 bp in an alternating manner, forming 2 different types of inter-rung interactions. The inter-rung 8-bp interaction was a strong-ordered interaction, whereas the inter-rung 12-bp interaction appeared to be weak or less-ordered, allowing Foxp3 to tolerate variable inter-rung spacings and confer a broad specificity for T(n)G-repeat-like sequences. The T(n)G repeat binding was conserved, as both Foxp3 orthologs and paralogs showed similar T(N)G repeat recognition and DNA bridging. </p>
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<p>Chatila et al. (2000), who referred to the FOXP3 gene as JM2, identified it by the positional-candidate approach as the likely site of mutations in the disorder they referred to as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD) and known by others as IPEX (304790). Chatila et al. (2000) detected a mutation in the FOXP3 gene in 2 unrelated kindreds. </p><p>Wildin et al. (2001) sequenced the human FOXP3 gene to determine whether the X-linked syndrome of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is the human equivalent of the scurfy mouse. They identified a novel mutation in each proband from 4 families with IPEX. Each mutation affected the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions. In a fifth family studied by Wildin et al. (2001) in which a variant form of IPEX mapped to the pericentromeric region of the X chromosome, no mutation in the FOXP3 gene was found. A later age of onset, waxing and waning clinical course, and occasional compatibility with prolonged survival had been reported in this family (Powell et al., 1982). This contrasted with the early, unrelenting course of the disorder seen in the other families. Wildin et al. (2001) suggested that this fifth family may harbor a noncoding FOXP3 mutation that affects transcriptional regulation or RNA splicing, resulting in a milder, environmentally dependent phenotype. </p><p>Bennett et al. (2001) also identified mutations in the FOXP3 gene in IPEX patients. They compared the mutations in FOXP3 with those in FOXE1 (602617) which result in a thyroid agenesis syndrome, and with those in FOXC1 (601090) which cause malformation of the anterior segment of the eye (Axenfeld-Rieger anomaly). </p><p>Bassuny et al. (2003) investigated the FOXP3 gene as a candidate for the type I diabetes susceptibility locus IDDMX (300136). They screened the FOXP3 gene for microsatellite and single nucleotide polymorphisms and performed an association study between the gene and type I diabetes in the Japanese population. One microsatellite polymorphism, (GT)n, was identified in intron 0, and a (GT)15 allele showed a significantly higher frequency in patients with type I diabetes than in controls (43.1% vs 32.6%, P = 0.0027). The evaluation of promoter/enhancer activity of the (GT)n polymorphism was performed by dual luciferase reporter assay. A significant difference in the enhancer activity between (GT)15 and (GT)16 dinucleotide repeats was detected. </p><p>Owen et al. (2003) studied 2 kindreds (21 subjects total) with 4 male infants (3 deceased) and 1 girl affected by IPEX. In 1 of the families they found a novel frameshift mutation in the FOXP3 gene (300292.0008). In the second family, the FOXP3 locus was excluded by recombination, and no FOXP3 mutations were found. They concluded that their data provided evidence for a nonlinked autosomal locus, suggesting genetic heterogeneity. </p><p>Bacchetta et al. (2006) studied the phenotype and in vitro function of CD4-positive T cells and CD4-positive/CD25(high) Treg cells in 4 children with IPEX. Flow cytometric analysis demonstrated that distribution and expression of various T-cell markers was comparable between patients and normal donor controls. Patient Treg cells showed different degrees of suppressive activity depending on the FOXP3 mutation, but none of the patients cells could suppress autologous responder cells. The defect was overcome after in vitro expansion of Treg cells. Of the 4 IPEX patients, only 1, who had a mutation in codon 1 (300292.0012) that resulted in no protein expression, had impaired transcription or translation of FOXP3. All patients had normal proliferative responses after T-cell receptor (TCR) stimulation, but they were unable to produce IL2 or IFNG. Bacchetta et al. (2006) concluded that Treg cells can be present in normal numbers in IPEX patients, but their capacity to suppress is impaired depending on the type of mutation, the strength of TCR stimuli, and the genotype of the effector T cells. </p>
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<p>'Scurfy' (sf) is an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth, and is characterized by overproliferation of CD4+/CD8- T lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines (Lyon et al., 1990; Clark et al., 1999). Similar to animals that lack expression of either Ctla4 (123890) or Tgf-beta (TGFB1; 190180), the pathology observed in sf mice seems to result from an inability to regulate properly CD4+/CD8- T-cell activity. Brunkow et al. (2001) determined that the Foxp3 gene is mutant in sf mice. A frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. </p><p>In mice overexpressing the Foxp3 gene, Khattri et al. (2001) observed fewer T cells. These remaining T cells had poor proliferative and cytolytic responses and poor IL2 production, although thymic development appeared normal. Histologic analysis showed that peripheral lymphoid organs, particularly lymph nodes, were relatively acellular. Khattri et al. (2001) concluded that excessive scurfin activity leads to a hypoactive immune state, suggesting that scurfin acts as a central regulator of T-cell activity. </p><p>By generating mice deficient in Foxp3, Fontenot et al. (2003) showed that Foxp3 is required for the development of CD4-positive/CD25-positive regulatory T cells. In addition, the IPEX-like lymphoproliferative autoimmune syndrome observed in Foxp3 -/- mice resulted from a deficiency in these regulatory T cells. The authors found that ectopic expression of Foxp3 activated a suppressor function in CD4-positive/CD25-negative T cells. Independently, Khattri et al. (2003) and Hori et al. (2003) reached similar conclusions. </p><p>Wan and Flavell (2007) noted that individuals with graft-versus-host disease, myasthenia gravis (see 254200), and multiple sclerosis have decreased FOXP3 expression. They generated a mouse model in which endogenous Foxp3 expression was attenuated in Tr cells. These mice were born at a mendelian ratio. Heterozygous females were fertile and phenotypically normal, but hemizygous males were barren and runted. Most males developed scaly skin, and nearly all developed a blepharitis-like condition. All mutant males died by 3 months of age due to an aggressive lymphoproliferative autoimmune syndrome, including drastically increased serum autoantibodies; however, thymic development was not affected. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their in vitro anergy was maintained, including preferential development into Th2-type effector cells even in a Th1-polarizing environment. Wan and Flavell (2007) concluded that decreased FOXP3 expression causes immune disease by subverting the suppressive function of Tr cells and converting Tr cells into effector cells. </p><p>Gavin et al. (2007) studied mouse T cells that actively transcribed a Foxp3-null allele, but lacked Foxp3 protein. Using flow cytometric and microarray analyses, they found that, although Foxp3 function was required for Tr suppressor cell activity, Foxp3 largely amplified and fixed preexisting molecular features of Tr cells. Furthermore, Foxp3 solidified Tr-cell lineage stability by modifying cell surface and signaling molecules, including Foxp3-dependent repression of phosphodiesterase-3b (PDE3B; 602047). Introduction of Pde3b into Tr cells and transfer of these cells to T-cell-deficient mice substantially reduced the number of Tr cells. Gavin et al. (2007) proposed that reduced PDE3B expression may be a unique marker of Tr cells. </p><p>To determine whether dysfunction or a lack of Treg cells is etiologically involved in pathogenesis of mouse scurfy and its human correlate, IPEX, Lahl et al. (2007) generated BAC-transgenic mice termed 'depletion of regulatory T cell' (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent fusion protein under control of Foxp3. Injection of DT allowed selective and efficient detection and inducible depletion of Foxp3-positive Treg cells without affecting Cd25-positive effector T cells. Histopathologic analysis showed that DT injection in newborn DEREG mice ablated Treg cells and led to development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Lahl et al. (2007) concluded that absence of Foxp3-positive Treg cells is sufficient to induce a scurfy-like phenotype. </p><p>Lund et al. (2008) examined a role for regulatory T cells (Tregs) in mucosal herpes simplex virus infection using Foxp3 knockin mice harboring Treg subsets tagged with either green fluorescent protein (GFP) or human diphtheria toxin receptor. They observed an accelerated fatal infection with increase in viral load in the mucosa and central nervous system after ablation of Tregs. Although augmented interferon production was detected in the draining lymph nodes in Treg-deprived mice, it was profoundly reduced at the infection site. This was associated with a delay in the arrival of natural killer cells, dendritic cells, and T cells to the site of infection and a sharp increase in proinflammatory chemokine levels in the draining lymph nodes. Lund et al. (2008) concluded that Tregs facilitate early protective responses to local viral infection by allowing a timely entry of immune cells into infected tissue. </p><p>Rowe et al. (2011) showed that expansion of Foxp3-positive Tregs during pregnancy in mice conferred enhanced susceptibility to Listeria and Salmonella bacterial infection. Treg ablation reduced susceptibility, but it broke maternal tolerance to fetal antigen and triggered fetal resorption. However, mice with Foxp3-positive cells and defective Il10 had reduced infection susceptibility without affecting pregnancy outcome. </p>
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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>13 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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<h4>
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<span class="mim-font">
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<strong>.0001 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, ARG397TRP
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<br />
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SNP: rs28935477,
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gnomAD: rs28935477,
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ClinVar: RCV000012160, RCV001290142
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Wildin et al. (2001) identified an arg397-to-trp mutation in the FOXP3 gene (due to 1189C-T) as the cause of IPEX (304790) in one of the patients previously reported by Levy-Lahad and Wildin (2001). The infant died at age 5 weeks with insulin-dependent diabetes mellitus, enteropathy, hypothyroidism, thrombocytopenia, and peritonitis. </p>
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</span>
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</div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, 20-BP DEL, 3-BP INS, NT1290
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<br />
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SNP: rs2147944039,
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ClinVar: RCV000012161
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an infant with IPEX (304790) reported by Peake et al. (1996), Wildin et al. (2001) identified a deletion-insertion mutation (1290-1309del, TGG ins) in the FOXP3 gene. The infant died at age 10 months with IDDM, enteropathy, anemia, lymphadenopathy, eczema, and sepsis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, PHE371CYS
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<br />
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SNP: rs122467169,
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ClinVar: RCV000012162
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a child with IPEX (304790), Wildin et al. (2001) identified a phe371-to-cys mutation in the FOXP3 gene. The patient had IDDM, enteropathy, anemia, and exfoliated dermatitis, and was surviving after bone marrow transplant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, ALA384THR
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<br />
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SNP: rs122467170,
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ClinVar: RCV000012163
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Wildin et al. (2001) identified an ala384-to-thr (A384T) mutation in the FOXP3 gene in an infant with IPEX (304790) who died at age 4 months with IDDM, enteropathy, hypothyroidism, thrombocytopenia, exfoliated dermatitis, and sepsis. </p><p>In a large family with cases of IPEX in multiple sibships through 4 generations, previously reported by Ferguson et al. (2000), Bennett et al. (2001) identified an A384T mutation in the FOXP3 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>
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<span class="mim-font">
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<strong>.0005 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, 2-BP DEL, 1481CT
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<br />
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SNP: rs1602679037,
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ClinVar: RCV000012164
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family of Japanese extraction, Bennett et al. (2001) found that the single male with IPEX (304790) had a CT dinucleotide deletion at positions 1481-1482 within the FOXP3 termination codon, predicting a frameshift and addition of 25 amino acids. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, IVS9DS, A-G, +4
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<br />
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SNP: rs1426535368,
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ClinVar: RCV000012165
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a kindred with IPEX (304790), Chatila et al. (2000) found an A-to-G substitution at position +4 of the 5-prime donor splice junction of intron 9 of the FOXP3 gene. The substitution was not present in 2 sibs and the parents, including the mother, indicating that it arose de novo. Sequence analysis of RT-PCR-amplified JM2 mRNA transcripts revealed skipping of JM2 exon 9 in transcripts of the index case. Exon 9 skipping resulted in a frameshift at codon 273 that gave rise to a premature stop signal at codon 286. This led to the generation of a truncated JM2 protein that lacked the forkhead homology domain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, GLU203DEL
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<br />
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SNP: rs122467171,
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ClinVar: RCV000012166, RCV004566720
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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 kindred with IPEX (304790), Chatila et al. (2000) found that affected males were hemizygous for a deletion of 3 bp in exon 7 of the FOXP3 gene, resulting in loss of the glutamic acid-201 residue. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, 1-BP DEL
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<br />
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SNP: rs2147949186,
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ClinVar: RCV000012167
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In the proband of a family with IPEX (304790), Owen et al. (2003) identified a single-base deletion of adenine at the second position of codon 76 in exon 2 of the FOXP3 gene. The mutation resulted in frameshift leading to a truncated protein product (108 residues vs 431 in wildtype). The mother and the proband's 2 healthy sisters were carriers of the mutation. The brother of the proband had died at 6 weeks of age and was found to have a lymphoid cell infiltration of the pancreas. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0009 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, PHE373ALA
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<br />
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SNP: rs122467172,
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gnomAD: rs122467172,
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ClinVar: RCV000012168
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with severe IPEX (304790) who presented with IDDM at age 2 weeks, Bacchetta et al. (2006) identified a double substitution (TT to GC) at nucleotide 1305 in exon 10 of the FOXP3 gene, resulting in a phe373-to-ala (F373A) substitution in the forkhead domain. The mutation was present in the patient's mother, but not in a healthy brother who served as the source of an HLA-identical bone marrow transplant that resolved all IPEX symptoms except the IDDM. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0010 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, PHE324LYS
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<br />
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SNP: rs122467173,
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ClinVar: RCV000012169
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Bacchetta et al. (2006) reported a patient with a mild form of IPEX (304790) who presented at age 4 months with severe enteritis and eczema and high serum IgE that resolved spontaneously. The patient had a T-to-C transition at nucleotide 970 in exon 9 of the FOXP3 gene, resulting in a phe324-to-leu (F324L) substitution in the forkhead domain, and a splice-site mutation, a C-to-T transition at nucleotide 543, affecting the 5-prime end of exon 5. The patient's healthy mother and an older brother who showed no symptoms of IPEX had the same mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, 543C-T
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<br />
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ClinVar: RCV000012170
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>See 300292.0010 and Bacchetta et al. (2006). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, MET1ILE
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<br />
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SNP: rs122467174,
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ClinVar: RCV000012171
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with severe IPEX (304790) who presented with neonatal IDDM, enteritis, recurrent skin infections, and hyper-IgE, Bacchetta et al. (2006) identified a G-to-A transition in the first codon of the FOXP3 gene, resulting in a met1-to-ile (M1I) substitution and no protein expression. The mutation was not present in the patient's mother. An HLA-identical bone marrow transplant from an unrelated donor appeared to resolve symptoms of autoimmune disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED</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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FOXP3, PRO367LEU
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<br />
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SNP: rs122467175,
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ClinVar: RCV000012172
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese patient with IPEX (304790), Suzuki et al. (2007) identified a pro367-to-leu (P367L) mutation in the FOX3P gene. The mutation occurred in the FKH domain, which is essential for DNA binding. The patient was born with severe SGA at 38 weeks' gestation. He presented with failure to thrive and was diagnosed with diabetes mellitus. He manifested intractable diarrhea and eczema, liver dysfunction with hyperammonemia, thrombocytopenia, and sepsis. At 14 weeks of age he suffered from acute renal failure resulting in congestive heart failure and pulmonary edema. He died at age 16 weeks. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bacchetta, R., Passerini, L., Gambineri, E., Dai, M., Allan, S. E., Perroni, L., Dagna-Bricarelli, F., Sartirana, C., Matthes-Martin, S., Lawitschka, A., Azzari, C., Ziegler, S. F., Levings, M. K., Roncarolo, M. G.
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<strong>A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes.</strong>
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Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D.
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<strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong>
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Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F.
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<strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong>
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<strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong>
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<p class="mim-text-font">
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Liu, B., Tahk, S., Yee, K. M., Fan, G., Shuai, K.
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<strong>The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.</strong>
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Bao Lige - updated : 07/22/2024<br>Ada Hamosh - updated : 09/22/2021<br>Ada Hamosh - updated : 10/28/2020<br>Ada Hamosh - updated : 09/23/2020<br>Ada Hamosh - updated : 12/12/2016<br>Paul J. Converse - updated : 06/12/2014<br>Paul J. Converse - updated : 2/11/2014<br>Paul J. Converse - updated : 9/13/2013<br>Ada Hamosh - updated : 10/24/2012<br>Patricia A. Hartz - updated : 9/21/2012<br>Paul J. Converse - updated : 3/15/2012<br>Ada Hamosh - updated : 5/19/2011<br>Paul J. Converse - updated : 1/7/2011<br>Ada Hamosh - updated : 12/28/2010<br>Paul J. Converse - updated : 10/26/2010<br>Paul J. Converse - updated : 9/14/2010<br>Paul J. Converse - updated : 8/3/2010<br>Ada Hamosh - updated : 3/5/2010<br>Matthew B. Gross - updated : 10/27/2009<br>Paul J. Converse - updated : 10/20/2009<br>Ada Hamosh - updated : 9/15/2009<br>Marla J. F. O'Neill - updated : 9/10/2009<br>Ada Hamosh - updated : 4/7/2009<br>Ada Hamosh - updated : 4/2/2009<br>Ada Hamosh - updated : 7/21/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>John A. Phillips, III - updated : 5/22/2008<br>Patricia A. Hartz - updated : 8/23/2007<br>Paul J. Converse - updated : 8/7/2007<br>Ada Hamosh - updated : 6/29/2007<br>Paul J. Converse - updated : 5/22/2007<br>Ada Hamosh - updated : 4/27/2007<br>Ada Hamosh - updated : 4/20/2007<br>Paul J. Converse - updated : 3/14/2007<br>Paul J. Converse - updated : 2/15/2007<br>Paul J. Converse - updated : 7/20/2006<br>Paul J. Converse - updated : 2/13/2006<br>Paul J. Converse - updated : 11/9/2005<br>Paul J. Converse - updated : 6/23/2005<br>John A. Phillips, III - updated : 4/1/2005<br>Natalie E. Krasikov - updated : 2/10/2004<br>Victor A. McKusick - updated : 9/22/2003<br>Paul J. Converse - updated : 3/26/2003<br>Paul J. Converse - updated : 2/26/2003<br>Paul J. Converse - updated : 2/15/2002<br>Victor A. McKusick - updated : 12/5/2001
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Victor A. McKusick : 1/2/2001
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