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Entry
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- *605515 - FORKHEAD BOX P1; FOXP1
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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">*605515</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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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</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="#cytogenetics">Cytogenetics</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/605515">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</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=ENSG00000114861;t=ENST00000649528" 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=27086" 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=605515" 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=ENSG00000114861;t=ENST00000649528" 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_001012505,NM_001244808,NM_001244810,NM_001244812,NM_001244813,NM_001244814,NM_001244815,NM_001244816,NM_001349337,NM_001349338,NM_001349340,NM_001349341,NM_001349342,NM_001349343,NM_001349344,NM_001370548,NM_032682,NR_146142,NR_146143" 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_001349338" 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=605515" 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=18518&isoform_id=18518_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/FOXP1" 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/7106820,12043714,12043718,13477187,14041833,14548062,14582216,18032256,18644886,18676893,21750965,22760094,27529939,30582125,33392735,47939602,48146445,50833688,50833690,51593351,60498987,119585893,119585894,119585895,119585896,119585897,119585898,119585899,119585900,119585901,119585902,119585903,119585904,126153370,193784138,194387304,348605219,348605223,348605227,348605229,348605231,348605235,549227701,1124885082,1158980000,1158980007,1158980009,1158980023,1158980025,1158980040,1678198097,1678207179,1678207193" 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/Q9H334" 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=27086" 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=ENSG00000114861;t=ENST00000649528" 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=FOXP1" 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=FOXP1" 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+27086" 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/FOXP1" 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:27086" 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/27086" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000649528.3&hgg_start=70954708&hgg_end=71583978&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3823" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3823" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605515[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=605515[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/FOXP1/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/ENSG00000114861" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=FOXP1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=FOXP1" 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=FOXP1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FOXP1&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/PA28241" 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:3823" 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:1914004" 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/FOXP1#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:1914004" 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/27086/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=27086" 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-041203-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:27086" 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=FOXP1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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605515
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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 P1; FOXP1
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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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GLUTAMINE-RICH FACTOR 1; QRF1
|
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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=FOXP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FOXP1</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/3/456?start=-3&limit=10&highlight=456">3p13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:70954708-71583978&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:70,954,708-71,583,978</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">
|
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<a href="/geneMap/3/456?start=-3&limit=10&highlight=456">
|
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3p13
|
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</a>
|
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</span>
|
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</td>
|
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|
|
|
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<td>
|
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<span class="mim-font">
|
|
Intellectual developmental disorder with language impairment with or without autistic features
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613670"> 613670 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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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">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605515" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605515" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<p>FOXP1 is a transcriptional repressor that plays a critical role in monocyte differentiation and macrophage function (<a href="#14" class="mim-tip-reference" title="Shi, C., Sakuma, M., Mooroka, T., Liscoe, A., Gao, H., Croce, K. J., Sharma, A., Kaplan, D., Greaves, D. R., Wang, Y., Simon, D. I. <strong>Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function.</strong> Blood 112: 4699-4711, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18799727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18799727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18799727[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/10.1182/blood-2008-01-137018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18799727">Shi et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18799727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Li, C., Tucker, P. W. <strong>DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.</strong> Proc. Nat. Acad. Sci. 90: 11583-11587, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8265594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8265594</a>] [<a href="https://doi.org/10.1073/pnas.90.24.11583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8265594">Li and Tucker (1993)</a> cloned a glutamine-rich factor, which they designated QRF1, that was expressed preferentially at the terminal differentiation stage of B cells and in skeletal muscle. The deduced 707-amino acid QRF1 protein contains an 84-amino acid segment that shows significant sequence homology with the DNA-binding domains of the hepatocyte nuclear factor-3/forkhead (see FOXA1; <a href="/entry/602294">602294</a>) family of proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8265594" 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 expression cloning using blood and testis cDNA libraries to identify the target of a monoclonal antibody (JC12), <a href="#1" class="mim-tip-reference" title="Banham, A. H., Beasley, N., Campo, E., Fernandez, P. L., Fidler, C., Gatter, K., Jones, M., Mason, D. Y., Prime, J. E., Trougouboff, P., Wood, K., Cordell, J. L. <strong>The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.</strong> Cancer Res. 61: 8820-8829, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751404</a>]" pmid="11751404">Banham et al. (2001)</a> obtained a full-length cDNA encoding FOXP1. The predicted 677-amino acid protein contains coiled-coil, glutamine-rich, and serine/threonine-rich domains in its N-terminal half; a central zinc finger domain; and coiled-coil, serine/threonine/proline-rich, winged helix, and acidic domains in its C-terminal half. FOXP1 also has numerous putative phosphorylation sites, 2 nuclear localization signals (NLSs) in its C-terminal half, and 2 PEST motif in its C-terminal acidic region. Multiple-tissue array analysis showed ubiquitous expression of FOXP1 in normal adult and fetal tissues, with highest expression in lymphoid and gastrointestinal tissues. Immunohistochemistry showed that FOXP1 protein was widely expressed, with a predominantly nuclear localization, in normal tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Wang, B., Lin, D., Li, C., Tucker, P. <strong>Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.</strong> J. Biol. Chem. 278: 24259-24268, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12692134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12692134</a>] [<a href="https://doi.org/10.1074/jbc.M207174200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12692134">Wang et al. (2003)</a> stated that there are 4 splice variants of mouse Foxp1, designated Foxp1a through Foxp1d. They identified and cloned Foxp1d, which encodes a Foxp1 isoform lacking the N-terminal polyglutamine domain found in Foxp1a and Foxp1b. Northern blot analysis and RNase protection assays showed tissue-specific expression of all 4 variants in mouse. Northern blot analysis of human tissues detected tissue-specific expression of FOXP1 variants, with highest levels in peripheral blood lymphocytes and in caudate nucleus of brain. Western blot analysis detected variable expression of Foxp1a, Foxp1c, and Foxp1d in mouse tissues, with high expression of all 3 isoforms in lung. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12692134" 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="#18" class="mim-tip-reference" title="Wang, B., Lin, D., Li, C., Tucker, P. <strong>Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.</strong> J. Biol. Chem. 278: 24259-24268, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12692134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12692134</a>] [<a href="https://doi.org/10.1074/jbc.M207174200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12692134">Wang et al. (2003)</a> found that mouse Foxp1a, Foxp1c, Foxp1d, and the related Foxp2 (<a href="/entry/605317">605317</a>) protein bound a 7-nucleotide core sequence, TATTT(G/A)T. These Foxp proteins repressed gene transcription via binding to this consensus site, which was identified within the SV40 and IL2 (<a href="/entry/147680">147680</a>) promoters. In some cases, the strength of Foxp1 repression was mediated by the polyglutamine domain. Mouse Foxp1 proteins also formed homodimers or heterodimers with subfamily members, and the conserved C2H2 zinc finger and leucine zipper motifs mediated dimerization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12692134" 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 genetic manipulations, <a href="#13" class="mim-tip-reference" title="Rousso, D. L., Gaber, Z. B., Wellik, D., Morrisey, E. E., Novitch, B. G. <strong>Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons.</strong> Neuron 59: 226-240, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667151</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18667151[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.neuron.2008.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18667151">Rousso et al. (2008)</a> demonstrated that Foxp1 established the pattern of LIM-homeodomain protein (see <a href="/entry/601999">601999</a>) expression in embryonic mice and, accordingly, organized motor axon projections, their connectivity with peripheral targets, and the establishment of motor pools. Hox proteins (see <a href="/entry/142950">142950</a>) dictated the pattern of Foxp1 expression in spinal cord, and both Foxp1 and Hox were required for segment-appropriate generation of motor columns and pools in mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18667151" 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="Shi, C., Sakuma, M., Mooroka, T., Liscoe, A., Gao, H., Croce, K. J., Sharma, A., Kaplan, D., Greaves, D. R., Wang, Y., Simon, D. I. <strong>Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function.</strong> Blood 112: 4699-4711, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18799727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18799727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18799727[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/10.1182/blood-2008-01-137018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18799727">Shi et al. (2008)</a> generated transgenic mice overexpressing human FOXP1 in monocyte/macrophage lineage cells. Circulating blood monocytes from these mice had reduced expression of macrophage colony-stimulating factor receptor (CSF1R; <a href="/entry/164770">164770</a>), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions were globally impaired, and osteoclastogenesis and bone resorption were attenuated. Forced overexpression of Csf1r reversed many of the deficits, suggesting that repression of Csf1r is likely the dominant mechanism responsible for FOXP1 effects on monocyte differentiation and macrophage function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18799727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association of FOXP1 with Cancer</em></strong></p><p>
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By analysis of a tumor/normal tissue expression array, <a href="#1" class="mim-tip-reference" title="Banham, A. H., Beasley, N., Campo, E., Fernandez, P. L., Fidler, C., Gatter, K., Jones, M., Mason, D. Y., Prime, J. E., Trougouboff, P., Wood, K., Cordell, J. L. <strong>The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.</strong> Cancer Res. 61: 8820-8829, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751404</a>]" pmid="11751404">Banham et al. (2001)</a> found that expression of FOXP1 was lower in colon tumors and higher in stomach and prostate tumors compared with matched normal tissues. Immunohistochemical analysis showed frequent loss of expression, increased expression, and cytoplasmic mislocalization of the predominantly nuclear FOXP1 protein in solid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751404" 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 immunohistochemical analysis of a diffuse large B-cell lymphoma (BCL) tissue microarray, <a href="#2" class="mim-tip-reference" title="Banham, A. H., Connors, J. M., Brown, P. J., Cordell, J. L., Ott, G., Sreenivasan, G., Farinha, P., Horsman, D. E., Gascoyne, R. D. <strong>Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.</strong> Clin. Cancer Res. 11: 1065-1072, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15709173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15709173</a>]" pmid="15709173">Banham et al. (2005)</a> found that untreated patients with a high percentage of FOXP1-positive nuclei had significantly reduced survival and earlier progression compared with FOXP1-negative patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15709173" 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>Of 275 BCLs, <a href="#8" class="mim-tip-reference" title="Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., Muller-Hermelink, H. K., Banham, A. H., Ott, G. <strong>Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. (Letter)</strong> Leukemia 20: 1300-1303, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16673020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16673020</a>] [<a href="https://doi.org/10.1038/sj.leu.2404244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16673020">Haralambieva et al. (2006)</a> found that only 5 (3 gastrointestinal, 1 thyroid, and 1 cervical lymph node) carried a chromosomal breakpoint in the FOXP1 gene and strong nuclear FOXP1 expression. All were diffuse large BCLs rather than marginal zone BCLs. <a href="#8" class="mim-tip-reference" title="Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., Muller-Hermelink, H. K., Banham, A. H., Ott, G. <strong>Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. (Letter)</strong> Leukemia 20: 1300-1303, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16673020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16673020</a>] [<a href="https://doi.org/10.1038/sj.leu.2404244" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16673020">Haralambieva et al. (2006)</a> concluded that genetic alterations at 3p13 are associated with strong FOXP1 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16673020" 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="#1" class="mim-tip-reference" title="Banham, A. H., Beasley, N., Campo, E., Fernandez, P. L., Fidler, C., Gatter, K., Jones, M., Mason, D. Y., Prime, J. E., Trougouboff, P., Wood, K., Cordell, J. L. <strong>The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.</strong> Cancer Res. 61: 8820-8829, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751404</a>]" pmid="11751404">Banham et al. (2001)</a> mapped the FOXP1 gene to chromosome 3p14.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751404" 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="#17" class="mim-tip-reference" title="Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M., Chott, A. <strong>T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.</strong> Leukemia 19: 652-658, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703784</a>] [<a href="https://doi.org/10.1038/sj.leu.2403644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703784">Streubel et al. (2005)</a> noted that 3 chromosomal translocations, t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), are associated with mucosa-associated lymphoid tissue (MALT) lymphomas. They identified a t(3;14)(p14;q32) in a case of MALT lymphoma of the thyroid. FISH studies showed that the IGH locus (<a href="/entry/147100">147100</a>) was rearranged, and long-distance inverse PCR identified FOXP1 as the partner gene on chromosome 3. Using FISH assays to screen 91 MALT lymphomas negative for 3 common translocations, <a href="#17" class="mim-tip-reference" title="Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M., Chott, A. <strong>T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.</strong> Leukemia 19: 652-658, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703784</a>] [<a href="https://doi.org/10.1038/sj.leu.2403644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703784">Streubel et al. (2005)</a> identified t(3;14)(p14;q32) in 9 cases (3 thyroid, 4 ocular adnexa, and 2 skin). Most t(3;14)(p14;q32)-positive MALT lymphomas also harbored additional genetic abnormalities, such as trisomy 3. All 4 of the MALT-associated translocations were mutually exclusive. Real-time RT-PCR analysis showed upregulated expression of FOXP1 in MALT cases with t(3;14)(p14;q32) or trisomy 3. <a href="#17" class="mim-tip-reference" title="Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M., Chott, A. <strong>T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.</strong> Leukemia 19: 652-658, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703784</a>] [<a href="https://doi.org/10.1038/sj.leu.2403644" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703784">Streubel et al. (2005)</a> concluded that FOXP1 is a translocation partner of IGH in a site-dependent subset of MALT lymphomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703784" 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="#5" class="mim-tip-reference" title="Carr, C. W., Moreno-De-Luca, D., Parker, C., Zimmerman, H. H., Ledbetter, N., Martin, C. L., Dobyns, W. B., Abdul-Rahman, O. A. <strong>Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency.</strong> Europ. J. Hum. Genet. 18: 1216-1220, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20571508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20571508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20571508[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2010.96" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20571508">Carr et al. (2010)</a> reported a boy with severe speech delay and delayed motor development (see <a href="/entry/613670">613670</a>) who carried a de novo heterozygous 1.0-Mb interstitial deletion of chromosome 3p14.1 that involved only the FOXP1 gene. The phenotype was confounded by a Chiari I malformation, which was surgically corrected at age 30 months. The patient had delayed gross motor skills and walked at 16 months. After surgery for the Chiari malformation, he had some improvement in motor skills. The most significant feature was speech delay with limited verbal output and difficulty in articulating entire words and multisyllabic speech, although he did not have a deficit in oromotor coordination. At age 4 years, he developed staring spells with motor arrest associated with epileptiform discharges. He had mild dysmorphic facial features, including broad forehead, hypertelorism, downslanting palpebral fissures, ptosis, short nose, broad nasal tip, and smooth philtrum. <a href="#5" class="mim-tip-reference" title="Carr, C. W., Moreno-De-Luca, D., Parker, C., Zimmerman, H. H., Ledbetter, N., Martin, C. L., Dobyns, W. B., Abdul-Rahman, O. A. <strong>Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency.</strong> Europ. J. Hum. Genet. 18: 1216-1220, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20571508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20571508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20571508[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2010.96" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20571508">Carr et al. (2010)</a> concluded that FOXP1 may play a role in the development of verbal and motor skills. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20571508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L. <strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong> Am. J. Hum. Genet. 87: 671-678, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20950788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20950788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20950788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20950788">Hamdan et al. (2010)</a> identified different de novo heterozygous mutations in the FOXP1 gene (<a href="#0001">605515.0001</a> and <a href="#0002">605515.0002</a>) in 2 unrelated children of French Canadian origin with moderately impaired intellectual development, expressive language deficits, and autistic features (IDDLA; <a href="/entry/613670">613670</a>). The first mutation (<a href="#0001">605515.0001</a>) was a deletion found by array-based comparative genomic hybridization of a cohort of 80 patients with autism spectrum disorders (ASD) and 30 with intellectual disability. The second mutation (R525X; <a href="#0002">605515.0002</a>) was found by direct sequencing of the FOXP1 gene in a cohort of 110 patients with intellectual disability, 84 with ASD, and 51 with both. <a href="#7" class="mim-tip-reference" title="Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L. <strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong> Am. J. Hum. Genet. 87: 671-678, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20950788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20950788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20950788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20950788">Hamdan et al. (2010)</a> chose to examine the FOXP1 gene specifically because of the role of the FOXP2 gene (<a href="/entry/605317">605317</a>) in a speech and language disorder (SPCH1; <a href="/entry/602081">602081</a>); patients with intellectual disability and ASD often show language impairment. The results indicated that disruption of FOXP1 has a global impact on brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20950788" 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 6.5-year-old boy with impaired intellectual development and language impairment but without autistic features, <a href="#10" class="mim-tip-reference" title="Le Fevre, A. K., Taylor, S., Malek, N. H., Horn, D., Carr, C. W., Abdul-Rahman, O. A., O'Donnell, S., Burgess, T., Shaw, M., Gecz, J., Bain, N., Fagan, K., Hunter, M. F. <strong>FOXP1 mutations cause intellectual disability and a recognizable phenotype.</strong> Am. J. Med. Genet. 161A: 3166-3175, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24214399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24214399</a>] [<a href="https://doi.org/10.1002/ajmg.a.36174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24214399">Le Fevre et al. (2013)</a> identified a de novo heterozygous intragenic deletion within the FOXP1 gene (<a href="#0003">605515.0003</a>), predicted to result in haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24214399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated children with impaired intellectual development, language impairment, and autistic features, <a href="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> identified 3 different de novo heterozygous mutations in the FOXP1 gene (<a href="#0005">605515.0005</a>-<a href="#0007">605515.0007</a>). The mutations, including 1 nonsense and 2 missense, were found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies showed that the mutations resulted in altered cellular localization and formation of protein aggregates, as well as loss of transcriptional repression activity. The variants retained the ability to interact with wildtype FOXP1, suggesting that they could exert a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" 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 exome sequencing, <a href="#12" class="mim-tip-reference" title="Moirangthem, A., Phadke, S. R. <strong>Novel FOXP1 pathogenic variants in two Indian subjects with syndromic intellectual disability.</strong> Am. J. Med. Genet. 185A: 1324-1327, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33427368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33427368</a>] [<a href="https://doi.org/10.1002/ajmg.a.62083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33427368">Moirangthem and Phadke (2021)</a> identified de novo heterozygous mutations in the FOXP1 gene in 2 unrelated Indian boys with intellectual developmental disorder with language impairment. Patient 1 had an insertion/deletion mutation (c.593_599delinsAGAAG, NM_032682) resulting in a frameshift and a premature stop codon (Leu198GlufsTer7), and patient 2 had a missense mutation (c.1556T-C, NM_032682.5) resulting in a leu519-to-pro (L519P) substitution in the highly conserved FOX domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33427368" 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 10-year-old girl with intellectual developmental disorder with language impairment, <a href="#4" class="mim-tip-reference" title="Benvenuto, M., Palumbo, P., Di Muro, E., Perrotta, C. S., Mazza, T., Mandara, G. M. L., Palumbo, O., Carella, M. <strong>Identification of a novel FOXP1 variant in a patient with hypotonia, intellectual disability, and severe speech impairment.</strong> Genes 14: 1958, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37895307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37895307</a>] [<a href="https://doi.org/10.3390/genes14101958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37895307">Benvenuto et al. (2023)</a> identified a de novo heterozygous nonsense mutation (Q344X) in exon 9 of the FOXP1 gene (c.1030C-T, NM_032682.6). The mutation was found by targeted gene panel sequencing and confirmed by Sanger sequencing. The variant was not present in the ESP6500, dbSNP, and gnomAD databases or in in-house controls and was classified as likely pathogenic by ACMG criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37895307" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Bekheirnia, M. R., Bekheirnia, N., Bainbridge, M. N., Gu, S., Coban Akdemir, Z. H., Gambin, T., Janzen, N. K., Jhangiani, S. N., Muzny, D. M., Michael, M., Brewer, E. D., Elenberg, E., and 24 others. <strong>Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.</strong> Genet. Med. 19: 412-420, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27657687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27657687</a>] [<a href="https://doi.org/10.1038/gim.2016.131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27657687">Bekheirnia et al. (2017)</a> performed whole-exome sequencing (WES) in 112 individuals from 62 families with a clinical diagnosis of congenital anomalies of kidney and urinary tract (CAKUT; see <a href="/entry/610805">610805</a>) and identified 1 deleterious de novo SNP in the FOXP1 gene. They then queried the clinical database at the Baylor Miraca Genetic Laboratory and identified 7 additional unrelated individuals with novel de novo single-nucleotide variants (SNVs) in FOXP1. There were 3 missense mutations, 4 frameshift, and 1 splice site mutation. Functional studies were not performed. All 8 individuals had neurodevelopmental phenotypes consistent with loss of function variants in FOXP1. However, 4 of the 8 individuals also had upper urinary tract defects, and 5 had defects in the lower genitourinary tract, including undescended testis, hypospadias, and neurogenic bladder. In addition, these patients have brain and heart involvement, which is consistent with the role of FOXP1 in the development of these organs. CNS malformations, including hydrocephaly, and cardiac defects were among the phenotypes of the patients in this study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27657687" 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="#9" class="mim-tip-reference" title="Hu, H., Wang, B., Borde, M., Nardone, J., Maika, S., Allred, L., Tucker, P. W., Rao, A. <strong>Foxp1 is an essential transcriptional regulator of B cell development.</strong> Nature Immun. 7: 819-826, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16819554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16819554</a>] [<a href="https://doi.org/10.1038/ni1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16819554">Hu et al. (2006)</a> found that mice lacking Foxp1 died at embryonic day 14.5 due to heart valve and outflow tract abnormalities. Reconstitution of Rag2 (<a href="/entry/179616">179616</a>)-deficient mice with Foxp1 -/- or Foxp1 +/- fetal liver cells resulted in decreased mature B cells, but normal thymocytes, in the recipients. Foxp1 -/- pro-B cells had reduced IgM, Rag1 (<a href="/entry/179615">179615</a>), and Rag2 expression, and V(D)J rearrangement was also impaired in Foxp1 -/- B cells. Chromatin immunoprecipitation and EMSA analyses showed that Foxp1 bound to Foxp site-2 (Fkh2) in the Erag enhancer, which is upstream of Rag2, in a B-lineage specific way. <a href="#9" class="mim-tip-reference" title="Hu, H., Wang, B., Borde, M., Nardone, J., Maika, S., Allred, L., Tucker, P. W., Rao, A. <strong>Foxp1 is an essential transcriptional regulator of B cell development.</strong> Nature Immun. 7: 819-826, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16819554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16819554</a>] [<a href="https://doi.org/10.1038/ni1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16819554">Hu et al. (2006)</a> concluded that FOXP1 influences B-cell development at an early stage, and that FOXP1 deficiency results in a phenotype that resembles double haploinsufficiency of E2A (TCF3; <a href="/entry/147141">147141</a>) and EBF (<a href="/entry/164343">164343</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16819554" 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="Feng, X., Ippolito, G. C., Tian, L., Wiehagen, K., Oh, S., Sambandam, A., Willen, J., Bunte, R. M., Maika, S. D., Harriss, J. V., Caton, A. J., Bhandoola, A., Tucker, P. W., Hu, H. <strong>Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development.</strong> Blood 115: 510-518, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965654[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/10.1182/blood-2009-07-232694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19965654">Feng et al. (2010)</a> generated mice with a conditional deletion of Foxp1 in double-positive thymocytes and found that peripheral Cd4 (see <a href="/entry/186940">186940</a>) and Cd8 (see <a href="/entry/186910">186910</a>) cells also lacked Foxp1 and that single-positive thymocytes acquired an activated phenotype in thymus. Peripheral cells also exhibited an activated phenotype and increased apoptosis and readily produced cytokines upon T-cell receptor engagement. <a href="#6" class="mim-tip-reference" title="Feng, X., Ippolito, G. C., Tian, L., Wiehagen, K., Oh, S., Sambandam, A., Willen, J., Bunte, R. M., Maika, S. D., Harriss, J. V., Caton, A. J., Bhandoola, A., Tucker, P. W., Hu, H. <strong>Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development.</strong> Blood 115: 510-518, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965654[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/10.1182/blood-2009-07-232694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19965654">Feng et al. (2010)</a> concluded that FOXP1 is an essential transcriptional regulator for thymocyte development and the generation of quiescent naive T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19965654" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605515[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</strong>
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<p>In a French Canadian girl (patient A, R0031608) with intellectual developmental disorder with language impairment and autistic features (IDDLA; <a href="/entry/613670">613670</a>), <a href="#7" class="mim-tip-reference" title="Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L. <strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong> Am. J. Hum. Genet. 87: 671-678, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20950788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20950788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20950788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20950788">Hamdan et al. (2010)</a> identified a de novo heterozygous 390-kb intragenic deletion in the FOXP1 gene. The deletion encompassed exons 4 to 14 of the longest FOXP1 isoform, including the translation initiation site and leucine zipper and zinc finger domains important for transcriptional activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20950788" 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">rs112795301 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs112795301;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=rs112795301" 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=rs112795301" 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=RCV000005214 OR RCV000760393 OR RCV003761738" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005214, RCV000760393, RCV003761738" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005214...</a>
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<p>In a French Canadian boy (patient B, R0024121) with intellectual developmental disorder with language impairment and autistic features (IDDLA; <a href="/entry/613670">613670</a>), <a href="#7" class="mim-tip-reference" title="Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L. <strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong> Am. J. Hum. Genet. 87: 671-678, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20950788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20950788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20950788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.09.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20950788">Hamdan et al. (2010)</a> identified a de novo heterozygous 1573C-T transition in the FOXP1 gene, resulting in an arg525-to-ter (R525X) substitution. The mutation was predicted to abolish the last 152 residues of the protein, including part of the forkhead DNA-binding (FHD) domain and a conserved nuclear localization signal. The mutation was not found in 570 controls. In vitro functional expression studies in HEK293 cells showed that the R525X mutant impaired the transcriptional repression ability of FOXP1, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20950788" 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="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> showed that the R525X mutant protein formed large cytoplasmic aggregates and was excluded from the nuclei in cellular transfection studies; these findings suggested misfolding of the aberrant protein. The R525X variant showed a complete loss of interaction with wildtype FOXP1 and FOXP2 (<a href="/entry/605317">605317</a>) and was unable to self-associate, suggesting haploinsufficiency as the pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND WITHOUT AUTISTIC FEATURES</strong>
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FOXP1, 190-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000144696" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144696" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144696</a>
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<p>In a 6.5-year-old boy with intellectual developmental disorder with language impairment but without autistic features (IDDLA; <a href="/entry/613670">613670</a>), <a href="#10" class="mim-tip-reference" title="Le Fevre, A. K., Taylor, S., Malek, N. H., Horn, D., Carr, C. W., Abdul-Rahman, O. A., O'Donnell, S., Burgess, T., Shaw, M., Gecz, J., Bain, N., Fagan, K., Hunter, M. F. <strong>FOXP1 mutations cause intellectual disability and a recognizable phenotype.</strong> Am. J. Med. Genet. 161A: 3166-3175, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24214399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24214399</a>] [<a href="https://doi.org/10.1002/ajmg.a.36174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24214399">Le Fevre et al. (2013)</a> identified a de novo heterozygous 190-kb intragenic deletion within the FOXP1 gene, resulting in the deletion of exons 6 to 13 and likely resulting in a truncated or nonfunctional protein, consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24214399" 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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND WITHOUT AUTISTIC FEATURES</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">rs587777855 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777855;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=rs587777855" 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=rs587777855" 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=RCV000144697 OR RCV005089672" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144697, RCV005089672" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144697...</a>
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<p>In a child (patient 41) with intellectual developmental disorder with language impairment (IDDLA; <a href="/entry/613670">613670</a>), <a href="#16" class="mim-tip-reference" title="Srivastava, S., Cohen, J. S., Vernon, H., Baranano, K., McClellan, R., Jamal, L., Naidu, S., Fatemi, A. <strong>Clinical whole exome sequencing in child neurology practice.</strong> Ann. Neurol. 76: 473-483, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25131622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25131622</a>] [<a href="https://doi.org/10.1002/ana.24251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25131622">Srivastava et al. (2014)</a> identified a de novo c.1600T-C transition in the FOXP1 gene, resulting in a trp534-to-arg (W534R) substitution. The patient was ascertained from a cohort of 78 patients with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the FOXP1 variant were not performed, but the phenotype was consistent with previous patients who had been shown to have FOXP1 haploinsufficiency. Additional features in this patient included macrocephaly, delayed development, and delayed myelination on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25131622" 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="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> showed that the mutant W534R protein had abnormal localization and formed cytoplasmic aggregates in cellular transfection studies. Luciferase reporter assays showed that the mutant protein had significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The W534R variant showed loss of interaction with wildtype FOXP1 and FOXP2 (<a href="/entry/605317">605317</a>) and had a reduced ability to self-associate, consistent with haploinsufficiency as the pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" 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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</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">rs869025202 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025202;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=rs869025202" 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=rs869025202" 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=RCV000207489 OR RCV001260764 OR RCV004701259" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207489, RCV001260764, RCV004701259" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207489...</a>
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<p>In an 11-year-old boy (patient 1) with intellectual developmental disorder with language impairment and autistic features (IDDLA; <a href="/entry/613670">613670</a>), but who did not fulfill the criteria for classic autism, <a href="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> identified a de novo heterozygous c.1393A-G transition (chr3.71,026,829A-G, GRCh37) in the FOXP1 gene, resulting in an arg465-t0-gly (R465G) substitution at a conserved residue in the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular expression studies showed that the mutant protein had abnormal localization and formed cytoplasmic and nuclear aggregates. Luciferase reporter assays showed that the mutant protein had significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The R565G variant retained the ability to interact with wildtype FOXP1 and FOXP2 (<a href="/entry/605317">605317</a>) and led to mislocalization of the wildtype proteins in nuclear aggregates, suggesting a possible dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" 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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</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">rs869025203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025203;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=rs869025203" 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=rs869025203" 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=RCV000207490 OR RCV001267938 OR RCV003417726 OR RCV004701260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207490, RCV001267938, RCV003417726, RCV004701260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207490...</a>
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<p>In a 7-year-old Dutch boy (patient 2) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; <a href="/entry/613670">613670</a>), <a href="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> identified a de novo heterozygous c.1540C-T transition (chr3.71,021,818C-T, GRCh37) in the FOXP1 gene, resulting in an arg514-to-cys (R514C) substitution at a conserved residue in the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular expression studies showed that the mutant protein had abnormal localization and formed cytoplasmic and nuclear aggregates. Luciferase reporter assays showed that the mutant protein had a significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The R514C variant retained the ability to interact with wildtype FOXP1 and FOXP2 (<a href="/entry/605317">605317</a>) and led to mislocalization of the wildtype proteins in nuclear aggregates, suggesting a possible dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</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">rs794727155 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727155;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=rs794727155" 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=rs794727155" 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=RCV000207487 OR RCV004701261" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207487, RCV004701261" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207487...</a>
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<p>In a 15-year-old Dutch girl (patient 3) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; <a href="/entry/613670">613670</a>), <a href="#15" class="mim-tip-reference" title="Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E. <strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong> Hum. Molec. Genet. 25: 546-557, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>] [<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26647308">Sollis et al. (2016)</a> identified a de novo heterozygous c.1317C-G transversion (chr3.71,027,010C-G, GRCh37) in the FOXP1 gene, resulting in a tyr439-to-ter (Y439X) substitution that truncates the protein between the leucine zipper dimerization domain and the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to result in FOXP1 haploinsufficiency, but no patient material was available to confirm nonsense-mediated mRNA decay of the altered transcript. In vitro studies showed that the Y439X variant formed large cytoplasmic aggregates and was absent from cell nuclei. Luciferase reporter assays showed that the mutant protein had a significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The Y439X variant retained the ability to interact with wildtype FOXP1 and FOXP2 (<a href="/entry/605317">605317</a>) and led to mislocalization of the wildtype proteins in cytoplasmic aggregates, suggesting a possible dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" 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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Banham, A. H., Beasley, N., Campo, E., Fernandez, P. L., Fidler, C., Gatter, K., Jones, M., Mason, D. Y., Prime, J. E., Trougouboff, P., Wood, K., Cordell, J. L.
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<strong>The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.</strong>
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Cancer Res. 61: 8820-8829, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751404</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.</strong>
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Clin. Cancer Res. 11: 1065-1072, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15709173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15709173</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15709173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bekheirnia, M. R., Bekheirnia, N., Bainbridge, M. N., Gu, S., Coban Akdemir, Z. H., Gambin, T., Janzen, N. K., Jhangiani, S. N., Muzny, D. M., Michael, M., Brewer, E. D., Elenberg, E., and 24 others.
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<strong>Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.</strong>
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Genet. Med. 19: 412-420, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27657687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27657687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27657687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/gim.2016.131" target="_blank">Full Text</a>]
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Benvenuto, M., Palumbo, P., Di Muro, E., Perrotta, C. S., Mazza, T., Mandara, G. M. L., Palumbo, O., Carella, M.
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<strong>Identification of a novel FOXP1 variant in a patient with hypotonia, intellectual disability, and severe speech impairment.</strong>
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Genes 14: 1958, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37895307/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37895307</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37895307" 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/10.3390/genes14101958" target="_blank">Full Text</a>]
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<a id="Carr2010" class="mim-anchor"></a>
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<div class="">
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Carr, C. W., Moreno-De-Luca, D., Parker, C., Zimmerman, H. H., Ledbetter, N., Martin, C. L., Dobyns, W. B., Abdul-Rahman, O. A.
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<strong>Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency.</strong>
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Europ. J. Hum. Genet. 18: 1216-1220, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20571508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20571508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20571508[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=20571508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2010.96" target="_blank">Full Text</a>]
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<a id="Feng2010" class="mim-anchor"></a>
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<div class="">
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Feng, X., Ippolito, G. C., Tian, L., Wiehagen, K., Oh, S., Sambandam, A., Willen, J., Bunte, R. M., Maika, S. D., Harriss, J. V., Caton, A. J., Bhandoola, A., Tucker, P. W., Hu, H.
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<strong>Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development.</strong>
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Blood 115: 510-518, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19965654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19965654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19965654[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=19965654" 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/10.1182/blood-2009-07-232694" target="_blank">Full Text</a>]
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<a id="Hamdan2010" class="mim-anchor"></a>
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Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L.
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<strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong>
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Am. J. Hum. Genet. 87: 671-678, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20950788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20950788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20950788[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=20950788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2010.09.017" target="_blank">Full Text</a>]
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<a id="Haralambieva2006" class="mim-anchor"></a>
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Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., Muller-Hermelink, H. K., Banham, A. H., Ott, G.
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<strong>Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. (Letter)</strong>
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Leukemia 20: 1300-1303, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16673020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16673020</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16673020" 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/sj.leu.2404244" target="_blank">Full Text</a>]
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<a id="Hu2006" class="mim-anchor"></a>
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Hu, H., Wang, B., Borde, M., Nardone, J., Maika, S., Allred, L., Tucker, P. W., Rao, A.
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<strong>Foxp1 is an essential transcriptional regulator of B cell development.</strong>
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Nature Immun. 7: 819-826, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16819554/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16819554</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16819554" 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/ni1358" target="_blank">Full Text</a>]
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<strong>FOXP1 mutations cause intellectual disability and a recognizable phenotype.</strong>
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Am. J. Med. Genet. 161A: 3166-3175, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24214399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24214399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24214399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36174" target="_blank">Full Text</a>]
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<a id="Li1993" class="mim-anchor"></a>
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Li, C., Tucker, P. W.
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<strong>DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8265594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8265594</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8265594" 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.90.24.11583" target="_blank">Full Text</a>]
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<a id="Moirangthem2021" class="mim-anchor"></a>
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<strong>Novel FOXP1 pathogenic variants in two Indian subjects with syndromic intellectual disability.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33427368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33427368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33427368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.62083" target="_blank">Full Text</a>]
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<strong>Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons.</strong>
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Neuron 59: 226-240, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667151</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18667151[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=18667151" 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.neuron.2008.06.025" target="_blank">Full Text</a>]
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<a id="Shi2008" class="mim-anchor"></a>
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Shi, C., Sakuma, M., Mooroka, T., Liscoe, A., Gao, H., Croce, K. J., Sharma, A., Kaplan, D., Greaves, D. R., Wang, Y., Simon, D. I.
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<strong>Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function.</strong>
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Blood 112: 4699-4711, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18799727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18799727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18799727[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=18799727" 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/10.1182/blood-2008-01-137018" target="_blank">Full Text</a>]
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<strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong>
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Hum. Molec. Genet. 25: 546-557, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26647308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26647308</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26647308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv495" target="_blank">Full Text</a>]
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Srivastava, S., Cohen, J. S., Vernon, H., Baranano, K., McClellan, R., Jamal, L., Naidu, S., Fatemi, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25131622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25131622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25131622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.24251" target="_blank">Full Text</a>]
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Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M., Chott, A.
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<strong>T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703784" 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/sj.leu.2403644" target="_blank">Full Text</a>]
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<strong>Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12692134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12692134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12692134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M207174200" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 08/13/2024
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Ada Hamosh - updated : 05/08/2019<br>Cassandra L. Kniffin - updated : 02/15/2017<br>Cassandra L. Kniffin - updated : 10/16/2014<br>Paul J. Converse - updated : 11/23/2011<br>Cassandra L. Kniffin - updated : 8/16/2011<br>Cassandra L. Kniffin - updated : 12/20/2010<br>Patricia A. Hartz - updated : 2/19/2010<br>Patricia A. Hartz - updated : 1/30/2009<br>Paul J. Converse - updated : 12/12/2006
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 1/2/2001
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alopez : 10/16/2024
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carol : 09/12/2024<br>carol : 08/13/2024<br>carol : 08/13/2024<br>carol : 02/14/2024<br>carol : 05/09/2019<br>carol : 05/08/2019<br>alopez : 05/08/2019<br>alopez : 05/07/2019<br>carol : 02/16/2017<br>ckniffin : 02/15/2017<br>carol : 10/20/2014<br>mcolton : 10/17/2014<br>ckniffin : 10/16/2014<br>ckniffin : 10/16/2014<br>mgross : 1/19/2012<br>terry : 11/23/2011<br>alopez : 8/18/2011<br>ckniffin : 8/16/2011<br>wwang : 12/21/2010<br>ckniffin : 12/20/2010<br>mgross : 2/24/2010<br>terry : 2/19/2010<br>mgross : 1/30/2009<br>mgross : 12/21/2006<br>terry : 12/12/2006<br>carol : 1/2/2001
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<strong>*</strong> 605515
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FORKHEAD BOX P1; FOXP1
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<em>Alternative titles; symbols</em>
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GLUTAMINE-RICH FACTOR 1; QRF1
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<strong><em>HGNC Approved Gene Symbol: FOXP1</em></strong>
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Cytogenetic location: 3p13
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:70,954,708-71,583,978 </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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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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3p13
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Intellectual developmental disorder with language impairment with or without autistic features
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<span class="mim-font">
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613670
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>FOXP1 is a transcriptional repressor that plays a critical role in monocyte differentiation and macrophage function (Shi et al., 2008). </p>
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<strong>Cloning and Expression</strong>
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<p>Li and Tucker (1993) cloned a glutamine-rich factor, which they designated QRF1, that was expressed preferentially at the terminal differentiation stage of B cells and in skeletal muscle. The deduced 707-amino acid QRF1 protein contains an 84-amino acid segment that shows significant sequence homology with the DNA-binding domains of the hepatocyte nuclear factor-3/forkhead (see FOXA1; 602294) family of proteins. </p><p>By expression cloning using blood and testis cDNA libraries to identify the target of a monoclonal antibody (JC12), Banham et al. (2001) obtained a full-length cDNA encoding FOXP1. The predicted 677-amino acid protein contains coiled-coil, glutamine-rich, and serine/threonine-rich domains in its N-terminal half; a central zinc finger domain; and coiled-coil, serine/threonine/proline-rich, winged helix, and acidic domains in its C-terminal half. FOXP1 also has numerous putative phosphorylation sites, 2 nuclear localization signals (NLSs) in its C-terminal half, and 2 PEST motif in its C-terminal acidic region. Multiple-tissue array analysis showed ubiquitous expression of FOXP1 in normal adult and fetal tissues, with highest expression in lymphoid and gastrointestinal tissues. Immunohistochemistry showed that FOXP1 protein was widely expressed, with a predominantly nuclear localization, in normal tissues. </p><p>Wang et al. (2003) stated that there are 4 splice variants of mouse Foxp1, designated Foxp1a through Foxp1d. They identified and cloned Foxp1d, which encodes a Foxp1 isoform lacking the N-terminal polyglutamine domain found in Foxp1a and Foxp1b. Northern blot analysis and RNase protection assays showed tissue-specific expression of all 4 variants in mouse. Northern blot analysis of human tissues detected tissue-specific expression of FOXP1 variants, with highest levels in peripheral blood lymphocytes and in caudate nucleus of brain. Western blot analysis detected variable expression of Foxp1a, Foxp1c, and Foxp1d in mouse tissues, with high expression of all 3 isoforms in lung. </p>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Wang et al. (2003) found that mouse Foxp1a, Foxp1c, Foxp1d, and the related Foxp2 (605317) protein bound a 7-nucleotide core sequence, TATTT(G/A)T. These Foxp proteins repressed gene transcription via binding to this consensus site, which was identified within the SV40 and IL2 (147680) promoters. In some cases, the strength of Foxp1 repression was mediated by the polyglutamine domain. Mouse Foxp1 proteins also formed homodimers or heterodimers with subfamily members, and the conserved C2H2 zinc finger and leucine zipper motifs mediated dimerization. </p><p>Using genetic manipulations, Rousso et al. (2008) demonstrated that Foxp1 established the pattern of LIM-homeodomain protein (see 601999) expression in embryonic mice and, accordingly, organized motor axon projections, their connectivity with peripheral targets, and the establishment of motor pools. Hox proteins (see 142950) dictated the pattern of Foxp1 expression in spinal cord, and both Foxp1 and Hox were required for segment-appropriate generation of motor columns and pools in mouse. </p><p>Shi et al. (2008) generated transgenic mice overexpressing human FOXP1 in monocyte/macrophage lineage cells. Circulating blood monocytes from these mice had reduced expression of macrophage colony-stimulating factor receptor (CSF1R; 164770), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions were globally impaired, and osteoclastogenesis and bone resorption were attenuated. Forced overexpression of Csf1r reversed many of the deficits, suggesting that repression of Csf1r is likely the dominant mechanism responsible for FOXP1 effects on monocyte differentiation and macrophage function. </p><p><strong><em>Association of FOXP1 with Cancer</em></strong></p><p>
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By analysis of a tumor/normal tissue expression array, Banham et al. (2001) found that expression of FOXP1 was lower in colon tumors and higher in stomach and prostate tumors compared with matched normal tissues. Immunohistochemical analysis showed frequent loss of expression, increased expression, and cytoplasmic mislocalization of the predominantly nuclear FOXP1 protein in solid tumors. </p><p>By immunohistochemical analysis of a diffuse large B-cell lymphoma (BCL) tissue microarray, Banham et al. (2005) found that untreated patients with a high percentage of FOXP1-positive nuclei had significantly reduced survival and earlier progression compared with FOXP1-negative patients. </p><p>Of 275 BCLs, Haralambieva et al. (2006) found that only 5 (3 gastrointestinal, 1 thyroid, and 1 cervical lymph node) carried a chromosomal breakpoint in the FOXP1 gene and strong nuclear FOXP1 expression. All were diffuse large BCLs rather than marginal zone BCLs. Haralambieva et al. (2006) concluded that genetic alterations at 3p13 are associated with strong FOXP1 expression. </p>
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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, Banham et al. (2001) mapped the FOXP1 gene to chromosome 3p14.1. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<p>Streubel et al. (2005) noted that 3 chromosomal translocations, t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), are associated with mucosa-associated lymphoid tissue (MALT) lymphomas. They identified a t(3;14)(p14;q32) in a case of MALT lymphoma of the thyroid. FISH studies showed that the IGH locus (147100) was rearranged, and long-distance inverse PCR identified FOXP1 as the partner gene on chromosome 3. Using FISH assays to screen 91 MALT lymphomas negative for 3 common translocations, Streubel et al. (2005) identified t(3;14)(p14;q32) in 9 cases (3 thyroid, 4 ocular adnexa, and 2 skin). Most t(3;14)(p14;q32)-positive MALT lymphomas also harbored additional genetic abnormalities, such as trisomy 3. All 4 of the MALT-associated translocations were mutually exclusive. Real-time RT-PCR analysis showed upregulated expression of FOXP1 in MALT cases with t(3;14)(p14;q32) or trisomy 3. Streubel et al. (2005) concluded that FOXP1 is a translocation partner of IGH in a site-dependent subset of MALT lymphomas. </p><p>Carr et al. (2010) reported a boy with severe speech delay and delayed motor development (see 613670) who carried a de novo heterozygous 1.0-Mb interstitial deletion of chromosome 3p14.1 that involved only the FOXP1 gene. The phenotype was confounded by a Chiari I malformation, which was surgically corrected at age 30 months. The patient had delayed gross motor skills and walked at 16 months. After surgery for the Chiari malformation, he had some improvement in motor skills. The most significant feature was speech delay with limited verbal output and difficulty in articulating entire words and multisyllabic speech, although he did not have a deficit in oromotor coordination. At age 4 years, he developed staring spells with motor arrest associated with epileptiform discharges. He had mild dysmorphic facial features, including broad forehead, hypertelorism, downslanting palpebral fissures, ptosis, short nose, broad nasal tip, and smooth philtrum. Carr et al. (2010) concluded that FOXP1 may play a role in the development of verbal and motor skills. </p>
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<strong>Molecular Genetics</strong>
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<p>Hamdan et al. (2010) identified different de novo heterozygous mutations in the FOXP1 gene (605515.0001 and 605515.0002) in 2 unrelated children of French Canadian origin with moderately impaired intellectual development, expressive language deficits, and autistic features (IDDLA; 613670). The first mutation (605515.0001) was a deletion found by array-based comparative genomic hybridization of a cohort of 80 patients with autism spectrum disorders (ASD) and 30 with intellectual disability. The second mutation (R525X; 605515.0002) was found by direct sequencing of the FOXP1 gene in a cohort of 110 patients with intellectual disability, 84 with ASD, and 51 with both. Hamdan et al. (2010) chose to examine the FOXP1 gene specifically because of the role of the FOXP2 gene (605317) in a speech and language disorder (SPCH1; 602081); patients with intellectual disability and ASD often show language impairment. The results indicated that disruption of FOXP1 has a global impact on brain development. </p><p>In a 6.5-year-old boy with impaired intellectual development and language impairment but without autistic features, Le Fevre et al. (2013) identified a de novo heterozygous intragenic deletion within the FOXP1 gene (605515.0003), predicted to result in haploinsufficiency. </p><p>In 3 unrelated children with impaired intellectual development, language impairment, and autistic features, Sollis et al. (2016) identified 3 different de novo heterozygous mutations in the FOXP1 gene (605515.0005-605515.0007). The mutations, including 1 nonsense and 2 missense, were found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro studies showed that the mutations resulted in altered cellular localization and formation of protein aggregates, as well as loss of transcriptional repression activity. The variants retained the ability to interact with wildtype FOXP1, suggesting that they could exert a dominant-negative effect. </p><p>By exome sequencing, Moirangthem and Phadke (2021) identified de novo heterozygous mutations in the FOXP1 gene in 2 unrelated Indian boys with intellectual developmental disorder with language impairment. Patient 1 had an insertion/deletion mutation (c.593_599delinsAGAAG, NM_032682) resulting in a frameshift and a premature stop codon (Leu198GlufsTer7), and patient 2 had a missense mutation (c.1556T-C, NM_032682.5) resulting in a leu519-to-pro (L519P) substitution in the highly conserved FOX domain. </p><p>In a 10-year-old girl with intellectual developmental disorder with language impairment, Benvenuto et al. (2023) identified a de novo heterozygous nonsense mutation (Q344X) in exon 9 of the FOXP1 gene (c.1030C-T, NM_032682.6). The mutation was found by targeted gene panel sequencing and confirmed by Sanger sequencing. The variant was not present in the ESP6500, dbSNP, and gnomAD databases or in in-house controls and was classified as likely pathogenic by ACMG criteria. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Bekheirnia et al. (2017) performed whole-exome sequencing (WES) in 112 individuals from 62 families with a clinical diagnosis of congenital anomalies of kidney and urinary tract (CAKUT; see 610805) and identified 1 deleterious de novo SNP in the FOXP1 gene. They then queried the clinical database at the Baylor Miraca Genetic Laboratory and identified 7 additional unrelated individuals with novel de novo single-nucleotide variants (SNVs) in FOXP1. There were 3 missense mutations, 4 frameshift, and 1 splice site mutation. Functional studies were not performed. All 8 individuals had neurodevelopmental phenotypes consistent with loss of function variants in FOXP1. However, 4 of the 8 individuals also had upper urinary tract defects, and 5 had defects in the lower genitourinary tract, including undescended testis, hypospadias, and neurogenic bladder. In addition, these patients have brain and heart involvement, which is consistent with the role of FOXP1 in the development of these organs. CNS malformations, including hydrocephaly, and cardiac defects were among the phenotypes of the patients in this study. </p>
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<strong>Animal Model</strong>
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<p>Hu et al. (2006) found that mice lacking Foxp1 died at embryonic day 14.5 due to heart valve and outflow tract abnormalities. Reconstitution of Rag2 (179616)-deficient mice with Foxp1 -/- or Foxp1 +/- fetal liver cells resulted in decreased mature B cells, but normal thymocytes, in the recipients. Foxp1 -/- pro-B cells had reduced IgM, Rag1 (179615), and Rag2 expression, and V(D)J rearrangement was also impaired in Foxp1 -/- B cells. Chromatin immunoprecipitation and EMSA analyses showed that Foxp1 bound to Foxp site-2 (Fkh2) in the Erag enhancer, which is upstream of Rag2, in a B-lineage specific way. Hu et al. (2006) concluded that FOXP1 influences B-cell development at an early stage, and that FOXP1 deficiency results in a phenotype that resembles double haploinsufficiency of E2A (TCF3; 147141) and EBF (164343). </p><p>Feng et al. (2010) generated mice with a conditional deletion of Foxp1 in double-positive thymocytes and found that peripheral Cd4 (see 186940) and Cd8 (see 186910) cells also lacked Foxp1 and that single-positive thymocytes acquired an activated phenotype in thymus. Peripheral cells also exhibited an activated phenotype and increased apoptosis and readily produced cytokines upon T-cell receptor engagement. Feng et al. (2010) concluded that FOXP1 is an essential transcriptional regulator for thymocyte development and the generation of quiescent naive T cells. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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<strong>7 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</strong>
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<span class="mim-text-font">
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FOXP1, 390-KB DEL
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<br />
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ClinVar: RCV004700256
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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 French Canadian girl (patient A, R0031608) with intellectual developmental disorder with language impairment and autistic features (IDDLA; 613670), Hamdan et al. (2010) identified a de novo heterozygous 390-kb intragenic deletion in the FOXP1 gene. The deletion encompassed exons 4 to 14 of the longest FOXP1 isoform, including the translation initiation site and leucine zipper and zinc finger domains important for transcriptional activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</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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FOXP1, ARG525TER
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<br />
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SNP: rs112795301,
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ClinVar: RCV000005214, RCV000760393, RCV003761738
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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 French Canadian boy (patient B, R0024121) with intellectual developmental disorder with language impairment and autistic features (IDDLA; 613670), Hamdan et al. (2010) identified a de novo heterozygous 1573C-T transition in the FOXP1 gene, resulting in an arg525-to-ter (R525X) substitution. The mutation was predicted to abolish the last 152 residues of the protein, including part of the forkhead DNA-binding (FHD) domain and a conserved nuclear localization signal. The mutation was not found in 570 controls. In vitro functional expression studies in HEK293 cells showed that the R525X mutant impaired the transcriptional repression ability of FOXP1, consistent with a loss of function. </p><p>Sollis et al. (2016) showed that the R525X mutant protein formed large cytoplasmic aggregates and was excluded from the nuclei in cellular transfection studies; these findings suggested misfolding of the aberrant protein. The R525X variant showed a complete loss of interaction with wildtype FOXP1 and FOXP2 (605317) and was unable to self-associate, suggesting haploinsufficiency as the pathogenic mechanism. </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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND WITHOUT AUTISTIC FEATURES</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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FOXP1, 190-KB DEL
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<br />
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ClinVar: RCV000144696
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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 6.5-year-old boy with intellectual developmental disorder with language impairment but without autistic features (IDDLA; 613670), Le Fevre et al. (2013) identified a de novo heterozygous 190-kb intragenic deletion within the FOXP1 gene, resulting in the deletion of exons 6 to 13 and likely resulting in a truncated or nonfunctional protein, consistent with haploinsufficiency. </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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND WITHOUT AUTISTIC FEATURES</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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FOXP1, TRP534ARG
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<br />
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SNP: rs587777855,
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ClinVar: RCV000144697, RCV005089672
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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 (patient 41) with intellectual developmental disorder with language impairment (IDDLA; 613670), Srivastava et al. (2014) identified a de novo c.1600T-C transition in the FOXP1 gene, resulting in a trp534-to-arg (W534R) substitution. The patient was ascertained from a cohort of 78 patients with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the FOXP1 variant were not performed, but the phenotype was consistent with previous patients who had been shown to have FOXP1 haploinsufficiency. Additional features in this patient included macrocephaly, delayed development, and delayed myelination on brain imaging. </p><p>Sollis et al. (2016) showed that the mutant W534R protein had abnormal localization and formed cytoplasmic aggregates in cellular transfection studies. Luciferase reporter assays showed that the mutant protein had significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The W534R variant showed loss of interaction with wildtype FOXP1 and FOXP2 (605317) and had a reduced ability to self-associate, consistent with haploinsufficiency as the pathogenic mechanism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FOXP1, ARG465GLY
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<br />
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SNP: rs869025202,
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ClinVar: RCV000207489, RCV001260764, RCV004701259
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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 an 11-year-old boy (patient 1) with intellectual developmental disorder with language impairment and autistic features (IDDLA; 613670), but who did not fulfill the criteria for classic autism, Sollis et al. (2016) identified a de novo heterozygous c.1393A-G transition (chr3.71,026,829A-G, GRCh37) in the FOXP1 gene, resulting in an arg465-t0-gly (R465G) substitution at a conserved residue in the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular expression studies showed that the mutant protein had abnormal localization and formed cytoplasmic and nuclear aggregates. Luciferase reporter assays showed that the mutant protein had significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The R565G variant retained the ability to interact with wildtype FOXP1 and FOXP2 (605317) and led to mislocalization of the wildtype proteins in nuclear aggregates, suggesting a possible dominant-negative effect. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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FOXP1, ARG514CYS
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<br />
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|
|
SNP: rs869025203,
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|
|
ClinVar: RCV000207490, RCV001267938, RCV003417726, RCV004701260
|
|
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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 7-year-old Dutch boy (patient 2) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; 613670), Sollis et al. (2016) identified a de novo heterozygous c.1540C-T transition (chr3.71,021,818C-T, GRCh37) in the FOXP1 gene, resulting in an arg514-to-cys (R514C) substitution at a conserved residue in the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular expression studies showed that the mutant protein had abnormal localization and formed cytoplasmic and nuclear aggregates. Luciferase reporter assays showed that the mutant protein had a significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The R514C variant retained the ability to interact with wildtype FOXP1 and FOXP2 (605317) and led to mislocalization of the wildtype proteins in nuclear aggregates, suggesting a possible dominant-negative effect. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FOXP1, TYR439TER
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<br />
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|
|
|
SNP: rs794727155,
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|
|
|
|
|
|
|
ClinVar: RCV000207487, RCV004701261
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old Dutch girl (patient 3) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; 613670), Sollis et al. (2016) identified a de novo heterozygous c.1317C-G transversion (chr3.71,027,010C-G, GRCh37) in the FOXP1 gene, resulting in a tyr439-to-ter (Y439X) substitution that truncates the protein between the leucine zipper dimerization domain and the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to result in FOXP1 haploinsufficiency, but no patient material was available to confirm nonsense-mediated mRNA decay of the altered transcript. In vitro studies showed that the Y439X variant formed large cytoplasmic aggregates and was absent from cell nuclei. Luciferase reporter assays showed that the mutant protein had a significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The Y439X variant retained the ability to interact with wildtype FOXP1 and FOXP2 (605317) and led to mislocalization of the wildtype proteins in cytoplasmic aggregates, suggesting a possible dominant-negative effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
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<div>
|
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<p />
|
|
</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">
|
|
Banham, A. H., Beasley, N., Campo, E., Fernandez, P. L., Fidler, C., Gatter, K., Jones, M., Mason, D. Y., Prime, J. E., Trougouboff, P., Wood, K., Cordell, J. L.
|
|
<strong>The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p.</strong>
|
|
Cancer Res. 61: 8820-8829, 2001.
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[PubMed: 11751404]
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</li>
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<li>
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<p class="mim-text-font">
|
|
Banham, A. H., Connors, J. M., Brown, P. J., Cordell, J. L., Ott, G., Sreenivasan, G., Farinha, P., Horsman, D. E., Gascoyne, R. D.
|
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<strong>Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.</strong>
|
|
Clin. Cancer Res. 11: 1065-1072, 2005.
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[PubMed: 15709173]
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<li>
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<p class="mim-text-font">
|
|
Bekheirnia, M. R., Bekheirnia, N., Bainbridge, M. N., Gu, S., Coban Akdemir, Z. H., Gambin, T., Janzen, N. K., Jhangiani, S. N., Muzny, D. M., Michael, M., Brewer, E. D., Elenberg, E., and 24 others.
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|
<strong>Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.</strong>
|
|
Genet. Med. 19: 412-420, 2017.
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[PubMed: 27657687]
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[Full Text: https://doi.org/10.1038/gim.2016.131]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Benvenuto, M., Palumbo, P., Di Muro, E., Perrotta, C. S., Mazza, T., Mandara, G. M. L., Palumbo, O., Carella, M.
|
|
<strong>Identification of a novel FOXP1 variant in a patient with hypotonia, intellectual disability, and severe speech impairment.</strong>
|
|
Genes 14: 1958, 2023.
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[PubMed: 37895307]
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[Full Text: https://doi.org/10.3390/genes14101958]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Carr, C. W., Moreno-De-Luca, D., Parker, C., Zimmerman, H. H., Ledbetter, N., Martin, C. L., Dobyns, W. B., Abdul-Rahman, O. A.
|
|
<strong>Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency.</strong>
|
|
Europ. J. Hum. Genet. 18: 1216-1220, 2010.
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[PubMed: 20571508]
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[Full Text: https://doi.org/10.1038/ejhg.2010.96]
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</p>
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<li>
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<p class="mim-text-font">
|
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Feng, X., Ippolito, G. C., Tian, L., Wiehagen, K., Oh, S., Sambandam, A., Willen, J., Bunte, R. M., Maika, S. D., Harriss, J. V., Caton, A. J., Bhandoola, A., Tucker, P. W., Hu, H.
|
|
<strong>Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development.</strong>
|
|
Blood 115: 510-518, 2010.
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[PubMed: 19965654]
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[Full Text: https://doi.org/10.1182/blood-2009-07-232694]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Hamdan, F. F., Daoud, H., Rochefort, D., Piton, A., Gauthier, J., Langlois, M., Foomani, G., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lafreniere, R. G., Lacaille, J.-C., Mottron, L., Drapeau, P., Beauchamp, M. H., Phillips, M. S., Fombonne, E., Rouleau, G. A., Michaud, J. L.
|
|
<strong>De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment.</strong>
|
|
Am. J. Hum. Genet. 87: 671-678, 2010.
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[PubMed: 20950788]
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[Full Text: https://doi.org/10.1016/j.ajhg.2010.09.017]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Haralambieva, E., Adam, P., Ventura, R., Katzenberger, T., Kalla, J., Holler, S., Hartmann, M., Rosenwald, A., Greiner, A., Muller-Hermelink, H. K., Banham, A. H., Ott, G.
|
|
<strong>Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation. (Letter)</strong>
|
|
Leukemia 20: 1300-1303, 2006.
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|
[PubMed: 16673020]
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[Full Text: https://doi.org/10.1038/sj.leu.2404244]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hu, H., Wang, B., Borde, M., Nardone, J., Maika, S., Allred, L., Tucker, P. W., Rao, A.
|
|
<strong>Foxp1 is an essential transcriptional regulator of B cell development.</strong>
|
|
Nature Immun. 7: 819-826, 2006.
|
|
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|
|
[PubMed: 16819554]
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|
|
[Full Text: https://doi.org/10.1038/ni1358]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Le Fevre, A. K., Taylor, S., Malek, N. H., Horn, D., Carr, C. W., Abdul-Rahman, O. A., O'Donnell, S., Burgess, T., Shaw, M., Gecz, J., Bain, N., Fagan, K., Hunter, M. F.
|
|
<strong>FOXP1 mutations cause intellectual disability and a recognizable phenotype.</strong>
|
|
Am. J. Med. Genet. 161A: 3166-3175, 2013.
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|
[PubMed: 24214399]
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[Full Text: https://doi.org/10.1002/ajmg.a.36174]
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</p>
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<li>
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<p class="mim-text-font">
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|
Li, C., Tucker, P. W.
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<strong>DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/fork head domain.</strong>
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|
Proc. Nat. Acad. Sci. 90: 11583-11587, 1993.
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[PubMed: 8265594]
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[Full Text: https://doi.org/10.1073/pnas.90.24.11583]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Moirangthem, A., Phadke, S. R.
|
|
<strong>Novel FOXP1 pathogenic variants in two Indian subjects with syndromic intellectual disability.</strong>
|
|
Am. J. Med. Genet. 185A: 1324-1327, 2021.
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|
|
[PubMed: 33427368]
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|
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[Full Text: https://doi.org/10.1002/ajmg.a.62083]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Rousso, D. L., Gaber, Z. B., Wellik, D., Morrisey, E. E., Novitch, B. G.
|
|
<strong>Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons.</strong>
|
|
Neuron 59: 226-240, 2008.
|
|
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|
|
[PubMed: 18667151]
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|
[Full Text: https://doi.org/10.1016/j.neuron.2008.06.025]
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</p>
|
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</li>
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Shi, C., Sakuma, M., Mooroka, T., Liscoe, A., Gao, H., Croce, K. J., Sharma, A., Kaplan, D., Greaves, D. R., Wang, Y., Simon, D. I.
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<strong>Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function.</strong>
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Sollis, E., Graham, S. A., Vino, A., Froehlich, H., Vreeburg, M., Dimitropoulou, D., Gilissen, C., Pfundt, R., Rappold, G. A., Brunner, H. G., Deriziotis, P., Fisher, S. E.
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<strong>Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder.</strong>
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Srivastava, S., Cohen, J. S., Vernon, H., Baranano, K., McClellan, R., Jamal, L., Naidu, S., Fatemi, A.
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<strong>Clinical whole exome sequencing in child neurology practice.</strong>
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Streubel, B., Vinatzer, U., Lamprecht, A., Raderer, M., Chott, A.
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<strong>T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma.</strong>
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Leukemia 19: 652-658, 2005.
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[PubMed: 15703784]
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Wang, B., Lin, D., Li, C., Tucker, P.
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<strong>Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.</strong>
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