4935 lines
430 KiB
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4935 lines
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Entry
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- *600635 - NK2 HOMEOBOX 1; NKX2-1
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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">*600635</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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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>
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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="#geneFamily">Gene Family</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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</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/600635">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>
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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=ENSG00000136352;t=ENST00000354822" 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=7080" 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=600635" 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=ENSG00000136352;t=ENST00000354822" 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_001079668,NM_003317" 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_001079668" 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=600635" 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=02798&isoform_id=02798_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/NKX2-1" 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/695583,767833,885890,1113817,1174819,1199865,1943579,2627169,2627171,2627173,3004850,4507715,14245740,31417473,32879889,118766339,119586260,119586261,119586262,119586263" 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/P43699" 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=7080" 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=ENSG00000136352;t=ENST00000354822" 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=NKX2-1" 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=NKX2-1" 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+7080" 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/NKX2-1" 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:7080" 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/7080" 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=chr14&hgg_gene=ENST00000354822.7&hgg_start=36516397&hgg_end=36520232&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11825" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/nkx2-1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600635[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=600635[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/NKX2-1/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/ENSG00000136352" 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=NKX2-1" 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=NKX2-1" 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=NKX2-1" 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=NKX2-1&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/PA36531" 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:11825" 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/FBgn0287186.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:108067" 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/NKX2-1#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:108067" 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/7080/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=7080" 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=WBGene00000447;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-010404-1" 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">
|
|
<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://reactome.org/content/query?q=NKX2-1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230306001<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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600635
|
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</span>
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</span>
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</div>
|
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
|
<span class="mim-font">
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NK2 HOMEOBOX 1; NKX2-1
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</span>
|
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
THYROID TRANSCRIPTION FACTOR 1; TITF1<br />
|
|
TTF1<br />
|
|
THYROID NUCLEAR FACTOR<br />
|
|
NK2, DROSOPHILA, HOMOLOG OF, A; NKX2A<br />
|
|
NK2.1, MOUSE, HOMOLOG OF<br />
|
|
THYROID-SPECIFIC ENHANCER-BINDING PROTEIN; TEBP
|
|
</span>
|
|
</h4>
|
|
</div>
|
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</div>
|
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NKX2-1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NKX2-1</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/14/179?start=-3&limit=10&highlight=179">14q13.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:36516397-36520232&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'})">14:36,516,397-36,520,232</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=188550,118700,610978" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/179?start=-3&limit=10&highlight=179">
|
|
14q13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Thyroid cancer, nonmedullary, 1}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/188550"> 188550 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
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</tr>
|
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|
|
|
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|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Chorea, hereditary benign
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/118700"> 118700 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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<p>The NKX2-1 gene encodes a transcription factor that is expressed during early development of thyroid, lung, and forebrain regions, particularly the basal ganglia and hypothalamus (summary by <a href="#23" class="mim-tip-reference" title="Thorwarth, A., Schnittert-Hubener, S., Schrumpf, P., Muller, I., Jyrch, S., Dame, C., Biebermann, H., Kleinau, G., Katchanov, J., Schuelke, M., Ebert, G., Steininger, A., and 17 others. <strong>Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum.</strong> J. Med. Genet. 51: 375-387, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24714694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24714694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24714694[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/10.1136/jmedgenet-2013-102248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24714694">Thorwarth et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24714694" 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>The protein referred to as thyroid transcription factor-1 (TTF1) by <a href="#11" class="mim-tip-reference" title="Guazzi, S., Price, M., De Felice, M., Damante, G., Mattei, M.-G., Di Lauro, R. <strong>Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity.</strong> EMBO J. 9: 3631-3639, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1976511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1976511</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07574.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1976511">Guazzi et al. (1990)</a> is a 38-kD nuclear protein that mediates thyroid-specific gene transcription. <a href="#11" class="mim-tip-reference" title="Guazzi, S., Price, M., De Felice, M., Damante, G., Mattei, M.-G., Di Lauro, R. <strong>Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity.</strong> EMBO J. 9: 3631-3639, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1976511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1976511</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07574.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1976511">Guazzi et al. (1990)</a> purified the protein from calf thyroids, obtained partial amino acid sequence and cloned the cDNA from a calf thyroid cDNA library using degenerate primers based on the peptide data. The human gene was obtained by <a href="#14" class="mim-tip-reference" title="Ikeda, K., Clark, J. C., Shaw-White, J. R., Stahlman, M. T., Boutell, C. J., Whitsett, J. A. <strong>Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.</strong> J. Biol. Chem. 270: 8108-8114, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713914</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713914">Ikeda et al. (1995)</a> and contains a homeobox domain and a 17-amino acid motif characteristic of the NKX2 family of transcription factors. TTF1 activates thyroglobulin (TG; <a href="/entry/188450">188450</a>) and thyroperoxidase (TPO; <a href="/entry/606765">606765</a>) gene transcription in thyroid adenocarcinomas and is expressed in epithelial cells of the rat thyroid. TTF1 also activates transcription of human surfactant protein B (SFTPB; <a href="/entry/178640">178640</a>) in the lung. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1976511+7713914" 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="Ikeda, K., Clark, J. C., Shaw-White, J. R., Stahlman, M. T., Boutell, C. J., Whitsett, J. A. <strong>Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.</strong> J. Biol. Chem. 270: 8108-8114, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713914</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713914">Ikeda et al. (1995)</a> screened a human genomic DNA cosmid library with the rat TTF1 cDNA. A subclone from the cosmid containing the gene was obtained and sequenced. The predicted 371-amino acid protein is 98% identical to the rat sequence. The predominant 2.4-kb RNA was shown to be expressed in pulmonary adenocarcinoma cells in addition to thyroid gland epithelium and the lung. TTF1 protein was detected in fetal lung as early as the eleventh week of gestation and localized in the nuclei of epithelial cells of the developing airways. After birth, expression was seen in type II epithelial cells in the alveoli and in some bronchiolar epithelial cells. When the 5-prime flanking region of the gene was placed in front of a luciferase reporter construct, activity could be measured in pulmonary adenocarcinoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7713914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Hamdan, H., Liu, H., Li, C., Jones, C., Lee, M., deLemos, R., Minoo, P. <strong>Structure of the human Nkx2.1 gene.</strong> Biochim. Biophys. Acta 1396: 336-348, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545595</a>] [<a href="https://doi.org/10.1016/s0167-4781(97)00210-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545595">Hamdan et al. (1998)</a> isolated several NKX2.1 cDNAs from human lung, which they grouped into 4 distinct classes. All the cDNAs but one encode a protein identical to that reported by <a href="#14" class="mim-tip-reference" title="Ikeda, K., Clark, J. C., Shaw-White, J. R., Stahlman, M. T., Boutell, C. J., Whitsett, J. A. <strong>Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.</strong> J. Biol. Chem. 270: 8108-8114, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713914</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713914">Ikeda et al. (1995)</a>. The remaining cDNA encodes a putative 402-amino acid protein with an N-terminal extension. Cell-free translation of a transcript encoding the longer protein resulted in polypeptides with apparent molecular masses of 44, 40, and 38 kD by SDS-PAGE. Translation of a transcript encoding the shorter protein resulted in polypeptides of 40 and 38 kD. <a href="#12" class="mim-tip-reference" title="Hamdan, H., Liu, H., Li, C., Jones, C., Lee, M., deLemos, R., Minoo, P. <strong>Structure of the human Nkx2.1 gene.</strong> Biochim. Biophys. Acta 1396: 336-348, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545595</a>] [<a href="https://doi.org/10.1016/s0167-4781(97)00210-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545595">Hamdan et al. (1998)</a> hypothesized that the different polypeptides result from the use of alternate ATG codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9545595+7713914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Holland, P. W. H., Booth, H. A. F., Bruford, E. A. <strong>Classification and nomenclature of all human homeobox genes.</strong> BMC Biol. 5: 47, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17963489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17963489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17963489[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/1741-7007-5-47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17963489">Holland et al. (2007)</a> stated that the NKX2-1 and NKX2-4 (<a href="/entry/607808">607808</a>) genes are collectively orthologous to Drosophila scro and comprise the Nk2.1 gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17963489" 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>Both TTF1 and PAX8 (<a href="/entry/167415">167415</a>) are thyroid-specific transcription factors that preferentially bind to the thyroglobulin and thyroperoxidase promoters, respectively (<a href="#1" class="mim-tip-reference" title="Acebron, A., Aza-Blanc, P., Rossi, D. L., Lamas, L., Santisteban, P. <strong>Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.</strong> J. Clin. Invest. 96: 781-785, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7635972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7635972</a>] [<a href="https://doi.org/10.1172/JCI118123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7635972">Acebron et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7635972" 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 yeast 2-hybrid analysis, <a href="#29" class="mim-tip-reference" title="Yang, Y.-S., Yang, M.-C. W., Wang, B., Weissler, J. C. <strong>BR22, a novel protein, interacts with thyroid transcription factor-1 and activates the human surfactant protein B promoter.</strong> Am. J. Resp. Cell Molec. Biol. 24: 30-37, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11152647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11152647</a>] [<a href="https://doi.org/10.1165/ajrcmb.24.1.4050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11152647">Yang et al. (2001)</a> showed that BR22 (CCDC59; <a href="/entry/619280">619280</a>) interacted with TTF1, and in vitro binding assays with purified recombinant proteins confirmed direct interaction. BR22 and TTF1 formed a complex in transfected HEK293 cells and acted synergistically to increase transactivation activity of the human surfactant protein B (SPB, or SFTPB; <a href="/entry/178640">178640</a>) promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11152647" 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 immunoprecipitation analysis, <a href="#28" class="mim-tip-reference" title="Yang, M.-C. W., Wang, B., Weissler, J. C., Margraf, L. R., Yang, Y. S. <strong>BR22, a 26 kDa thyroid transcription factor-1 associated protein (TAP26), is expressed in human lung cells.</strong> Europ. Resp. J. 22: 28-34, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12882447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12882447</a>] [<a href="https://doi.org/10.1183/09031936.03.00117702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12882447">Yang et al. (2003)</a> showed that endogenous TAP26 and TTF1 interacted and formed a complex in H441 human lung epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12882447" 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 chromatin immunoprecipitation analysis, <a href="#27" class="mim-tip-reference" title="Yang, M.-C., Guo, Y., Liu, C.-C., Weissler, J. C., Yang, Y.-S. <strong>The TTF-1/TAP26 complex differentially modulates surfactant protein-B (SP-B) and -C (SP-C) promoters in lung cells.</strong> Biochem. Biophys. Res. Commun. 344: 484-490, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16630564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16630564</a>] [<a href="https://doi.org/10.1016/j.bbrc.2006.03.158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16630564">Yang et al. (2006)</a> identified TAP26 as a coactivator with TTF1 on both the SPB and SPC (SFTPC; <a href="/entry/178620">178620</a>) promoter complexes. The TTF1/TAP26 complex stimulated both SPB and SPC promoter activities in H441 cells in a dose-dependent manner. TAP26 alone induced SPB promoter activity, but not SPC promoter activity, in H441 cells. However, in mouse lung MLE12 cells, the TTF1/TAP26 complex or TAP26 alone stimulated only SPB promoter activity, but not SPC promoter activity. The findings indicated that the mechanism for response of the SPC promoter to the complex was different from that of the SPB promoter, and that neither TTF1 nor TAP26 was the limiting factor for the SPC promoter in MLE12 cells. RT-PCR analysis showed that expression of TTF1 and TAP26 was lower in H441 cells compared with MLE12 cells, suggesting that TTF1/TAP26 complex-activated SPC promoter activity was already optimized in MLE12 cells, but not in H441 cells. In addition, SPC promoter stimulation by the TTF1/TAP26 complex in MLE12 cells required TTF1-binding sites T4 and T5 in the proximal region of the SPC promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16630564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Zhu, N. L., Li, C., Xiao, J., Minoo, P. <strong>NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells.</strong> Gene 327: 25-36, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14960358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14960358</a>] [<a href="https://doi.org/10.1016/j.gene.2003.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14960358">Zhu et al. (2004)</a> presented evidence that mouse Titf1, which they called Nkx2.1, is a potential upstream regulator of Bmp4 (<a href="/entry/112262">112262</a>) expression in lung. Titf1 and Bmp4 were coexpressed in developing mouse lungs. Using EMSA and cotransfection assays in mammalian lung epithelial cells, <a href="#30" class="mim-tip-reference" title="Zhu, N. L., Li, C., Xiao, J., Minoo, P. <strong>NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells.</strong> Gene 327: 25-36, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14960358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14960358</a>] [<a href="https://doi.org/10.1016/j.gene.2003.11.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14960358">Zhu et al. (2004)</a> identified functional cis-active Titf1 response elements in both Bmp4 promoter regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14960358" 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="Dentice, M., Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., Di Lauro, R., Rossi, G., Fenzi, G., Salvatore, D. <strong>Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells.</strong> Molec. Cell. Biol. 25: 10171-10182, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16260629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16260629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16260629[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/10.1128/MCB.25.22.10171-10182.2005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16260629">Dentice et al. (2005)</a> determined that Titf1 directly controls expression of the pendrin gene (SLC26A4; <a href="/entry/605646">605646</a>) in rat thyroid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16260629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To gain insight into human thyroid development and thyroid dysgenesis-associated malformations, <a href="#24" class="mim-tip-reference" title="Trueba, S. S., Auge, J., Mattei, G., Etchevers, H., Martinovic, J., Czernichow, P., Vekemans, M., Polak, M., Attie-Bitach, T. <strong>PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.</strong> J. Clin. Endocr. Metab. 90: 455-462, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15494458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15494458</a>] [<a href="https://doi.org/10.1210/jc.2004-1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15494458">Trueba et al. (2005)</a> studied the expression patterns of the PAX8, TITF1, and FOXE1 (<a href="/entry/602617">602617</a>) genes during human development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. The expression patterns of these genes in human show some differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. The authors concluded that the expression patterns of these 3 genes correlate well with the phenotypes observed in patients carrying mutations of the corresponding gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15494458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Garcia-Barcelo, M., Ganster, R. W., Lui, V. C. H., Leon, T. Y. Y., So, M.-T., Lau, A. M. F., Fu, M., Sham, M.-H., Knight, J., Zannini, M. S., Sham, P. C., Tam, P. K. H. <strong>TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.</strong> Hum. Molec. Genet. 14: 191-204, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548547</a>] [<a href="https://doi.org/10.1093/hmg/ddi015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548547">Garcia-Barcelo et al. (2005)</a> localized TITF1 to the myenteric and submucosa plexuses in adult human colon and to the mesenchyme of embryonic stomach, where it colocalized with RET (<a href="/entry/164761">164761</a>). Expression of TITF1 activated RET transcription via a predicted TITF1-binding site in the RET promoter region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15548547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., Shah, K., Sato, M., and 58 others. <strong>Characterizing the cancer genome in lung adenocarcinoma.</strong> Nature 450: 893-898, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17982442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17982442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17982442[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/nature06358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17982442">Weir et al. (2007)</a> reported a large-scale project to characterize copy number alterations in primary lung adenocarcinomas. By analysis of 371 tumors using dense single-nucleotide polymorphism arrays, <a href="#25" class="mim-tip-reference" title="Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., Shah, K., Sato, M., and 58 others. <strong>Characterizing the cancer genome in lung adenocarcinoma.</strong> Nature 450: 893-898, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17982442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17982442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17982442[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/nature06358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17982442">Weir et al. (2007)</a> identified 57 significantly recurrent events. <a href="#25" class="mim-tip-reference" title="Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., Shah, K., Sato, M., and 58 others. <strong>Characterizing the cancer genome in lung adenocarcinoma.</strong> Nature 450: 893-898, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17982442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17982442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17982442[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/nature06358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17982442">Weir et al. (2007)</a> found that 26 of 39 autosomal chromosome arms showed consistent large-scale copy number gain or loss, of which only a handful had been linked to a specific gene. They also identified 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only 6 of these focal events were associated with mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, was found in about 12% of samples. On the basis of genomic and functional analyses, <a href="#25" class="mim-tip-reference" title="Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., Shah, K., Sato, M., and 58 others. <strong>Characterizing the cancer genome in lung adenocarcinoma.</strong> Nature 450: 893-898, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17982442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17982442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17982442[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/nature06358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17982442">Weir et al. (2007)</a> identified NKX2-1, which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate protooncogene involved in a significant fraction of lung adenocarcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17982442" 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="#22" class="mim-tip-reference" title="Taniguchi, H., Lu, J., Huang, Z. J. <strong>The spatial and temporal origin of chandelier cells in mouse neocortex.</strong> Science 339: 70-74, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23180771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23180771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23180771[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23180771">Taniguchi et al. (2013)</a> followed the development trajectory of chandelier cells, the most distinct interneurons that innervate the axon initial segment of pyramidal neurons and control action potential initiation. Chandelier cells mainly derive from the ventral germinal zone of the lateral ventricle during late gestation and require the homeodomain protein Nkx2.1 for their specification. They migrate with stereotyped routes, and schedule and achieve specific laminar distribution in the cortex. <a href="#22" class="mim-tip-reference" title="Taniguchi, H., Lu, J., Huang, Z. J. <strong>The spatial and temporal origin of chandelier cells in mouse neocortex.</strong> Science 339: 70-74, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23180771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23180771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23180771[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1227622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23180771">Taniguchi et al. (2013)</a> concluded that the developmental specification of this bona fide interneuron type likely contributes to the assembly of a cortical circuit motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23180771" 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="#14" class="mim-tip-reference" title="Ikeda, K., Clark, J. C., Shaw-White, J. R., Stahlman, M. T., Boutell, C. J., Whitsett, J. A. <strong>Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.</strong> J. Biol. Chem. 270: 8108-8114, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713914</a>] [<a href="https://doi.org/10.1074/jbc.270.14.8108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713914">Ikeda et al. (1995)</a> determined that the TITF1 gene spans approximately 3.3 kb and contains 2 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7713914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Hamdan, H., Liu, H., Li, C., Jones, C., Lee, M., deLemos, R., Minoo, P. <strong>Structure of the human Nkx2.1 gene.</strong> Biochim. Biophys. Acta 1396: 336-348, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545595</a>] [<a href="https://doi.org/10.1016/s0167-4781(97)00210-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545595">Hamdan et al. (1998)</a> determined that the TITF1 gene contains 3 exons. They identified 2 regions that mediate basal promoter activity in lung epithelial cells, one within the first intron, and the other 5-prime to the first exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545595" 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="Guazzi, S., Price, M., De Felice, M., Damante, G., Mattei, M.-G., Di Lauro, R. <strong>Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity.</strong> EMBO J. 9: 3631-3639, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1976511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1976511</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07574.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1976511">Guazzi et al. (1990)</a> mapped the TITF1 gene by in situ hybridization to mouse chromosome 12C1-C3 and in humans to chromosome 14q12-q21 with most of the grains localized to 14q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1976511" 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="#26" class="mim-tip-reference" title="Winslow, M. M., Dayton, T. L., Verhaak, R. G. W., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., Jacks, T. <strong>Suppression of lung adenocarcinoma progression by Nkx2-1.</strong> Nature 473: 101-104, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21471965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21471965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21471965[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/nature09881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21471965">Winslow et al. (2011)</a> modeled human lung adenocarcinoma, which frequently harbors activating point mutations in KRAS (<a href="/entry/190070">190070</a>) and inactivation of the p53 (<a href="/entry/191170">191170</a>) pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumors are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed <a href="#26" class="mim-tip-reference" title="Winslow, M. M., Dayton, T. L., Verhaak, R. G. W., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., Jacks, T. <strong>Suppression of lung adenocarcinoma progression by Nkx2-1.</strong> Nature 473: 101-104, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21471965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21471965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21471965[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/nature09881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21471965">Winslow et al. (2011)</a> to distinguish metastatic from nonmetastatic tumors and determine the gene expression alterations that distinguish these tumor types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumors. Gain- and loss-of-function experiments in cells derived from metastatic and nonmetastatic tumors demonstrated that Nkx2-1 controls tumor differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumors at defined developmental stages, and functional complementation experiments indicated that Nkx2-1 constrains tumors in part by repressing the embryonically restricted chromatin regulator Hmga2 (<a href="/entry/600698">600698</a>). Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas had focused attention on its oncogenic function, <a href="#26" class="mim-tip-reference" title="Winslow, M. M., Dayton, T. L., Verhaak, R. G. W., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., Jacks, T. <strong>Suppression of lung adenocarcinoma progression by Nkx2-1.</strong> Nature 473: 101-104, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21471965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21471965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21471965[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/nature09881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21471965">Winslow et al. (2011)</a> stated that their data specifically linked Nkx2-1 downregulation to loss of differentiation, enhanced tumor seeding ability, and increased metastatic proclivity. <a href="#26" class="mim-tip-reference" title="Winslow, M. M., Dayton, T. L., Verhaak, R. G. W., Kim-Kiselak, C., Snyder, E. L., Feldser, D. M., Hubbard, D. D., DuPage, M. J., Whittaker, C. A., Hoersch, S., Yoon, S., Crowley, D., Bronson, R. T., Chiang, D. Y., Meyerson, M., Jacks, T. <strong>Suppression of lung adenocarcinoma progression by Nkx2-1.</strong> Nature 473: 101-104, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21471965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21471965</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21471965[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/nature09881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21471965">Winslow et al. (2011)</a> concluded that the oncogenic and suppressive functions of Nkx2-1 in the same tumor type substantiate its role as a dual function lineage factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21471965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Acebron, A., Aza-Blanc, P., Rossi, D. L., Lamas, L., Santisteban, P. <strong>Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.</strong> J. Clin. Invest. 96: 781-785, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7635972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7635972</a>] [<a href="https://doi.org/10.1172/JCI118123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7635972">Acebron et al. (1995)</a> reported 3 sibs, a woman and 2 men, with congenital hypothyroid goiter due to defective thyroglobulin synthesis. In the sister, Northern blot analysis, RT-PCR, and electrophoretic mobility shift assays demonstrated virtual absence of TTF1 expression. She had normal levels of PAX8 mRNA and thyroperoxidase mRNA but very low levels of thyroglobulin mRNA. <a href="#1" class="mim-tip-reference" title="Acebron, A., Aza-Blanc, P., Rossi, D. L., Lamas, L., Santisteban, P. <strong>Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.</strong> J. Clin. Invest. 96: 781-785, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7635972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7635972</a>] [<a href="https://doi.org/10.1172/JCI118123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7635972">Acebron et al. (1995)</a> stated that this was the first reported evidence of congenital goiter with thyroglobulin synthesis defect due to low expression of TTF1. The parents were unaffected and were not known to be related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7635972" 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 172 sporadic Chinese patients with Hirschsprung disease (HSCR; <a href="/entry/142623">142623</a>), <a href="#9" class="mim-tip-reference" title="Garcia-Barcelo, M., Ganster, R. W., Lui, V. C. H., Leon, T. Y. Y., So, M.-T., Lau, A. M. F., Fu, M., Sham, M.-H., Knight, J., Zannini, M. S., Sham, P. C., Tam, P. K. H. <strong>TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.</strong> Hum. Molec. Genet. 14: 191-204, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15548547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15548547</a>] [<a href="https://doi.org/10.1093/hmg/ddi015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15548547">Garcia-Barcelo et al. (2005)</a> identified HSCR-associated RET (<a href="/entry/164761">164761</a>) promoter SNPs that were highly correlated with disease. They determined that the promoter SNPs overlapped a predicted cis-acting TITF1-binding site. Functional analysis demonstrated that the HSCR-associated alleles decreased RET transcription. TITF1 expression activated transcription from the RET promoter, and TITF1-activated RET transcription was reduced by the HSCR-associated SNPs. The authors identified a Chinese patient with HSCR who was heterozygous for a gly322-to-ser (G322S) mutation in the TITF1 gene. The patient did not harbor a mutation in any of the known HSCR-associated genes. Mutant TITF1 specifically decreased the function of the TITF1 5E isoform when assessed on the HSCR-associated RET haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15548547" 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="#10" class="mim-tip-reference" title="Garcia-Barcelo, M.-M., Lau, D. K., Ngan, E. S., Leon, T. Y., Liu, T., So, M., Miao, X., Lui, V. C., Wong, K. K., Ganster, R. W., Cass, D. T., Croaker, G. D. H., Tam, P. K. <strong>Evaluation of the thyroid transcription factor-1 gene (TITF1) as a Hirschsprung's disease locus.</strong> Ann. Hum. Genet. 71: 746-754, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17640327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17640327</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2007.00384.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17640327">Garcia-Barcelo et al. (2007)</a> analyzed the TITF1 gene in an additional 102 Chinese and 70 Australian Caucasian HSCR patients and identified a met3-to-leu (M3L) mutation in 2 of the Australian patients that was not found in 194 Chinese and 60 Caucasian unrelated controls. In vitro functional studies showed that M3L completely abolished the activation of RET by TITF1, irrespective of the HSCR-associated haplotype in the RET promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17640327" 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>Benign Hereditary Chorea</em></strong></p><p>
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In affected members of a family with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P. <strong>Mutations in TITF-1 are associated with benign hereditary chorea.</strong> Hum. Molec. Genet. 11: 971-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971878</a>] [<a href="https://doi.org/10.1093/hmg/11.8.971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971878">Breedveld et al. (2002)</a> identified a heterozygous 1.2-Mb deletion including the TITF1 gene. The authors also reported other BHC families with heterozygous point mutations in the TITF1 gene (see, e.g., <a href="#0001">600635.0001</a>-<a href="#0004">600635.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971878" 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>Choreoathetosis and Congenital Hypothyroidism with or without Pulmonary Dysfunction</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Devriendt, K., Vanhole, C., Matthijs, G., de Zegher, F. <strong>Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. (Letter)</strong> New Eng. J. Med. 338: 1317-1318, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9565498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9565498</a>] [<a href="https://doi.org/10.1056/NEJM199804303381817" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9565498">Devriendt et al. (1998)</a> identified deletion of the TTF1 gene in an infant with choreoathetosis and congenital hypothyroidism with pulmonary dysfunction (CAHTP; <a href="/entry/610978">610978</a>). The infant presented with respiratory failure, hypotonia, and truncal ataxia. <a href="#15" class="mim-tip-reference" title="Iwatani, N., Mabe, H., Devriendt, K., Kodama, M., Miike, T. <strong>Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure.</strong> J. Pediat. 137: 272-276, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10931427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10931427</a>] [<a href="https://doi.org/10.1067/mpd.2000.107111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10931427">Iwatani et al. (2000)</a> reported deletion of the gene in 2 sibs with hypothyroidism and respiratory failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10931427+9565498" 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-year-old boy with dyskinesia, neonatal respiratory distress, and compensated hypothyroidism, <a href="#20" class="mim-tip-reference" title="Pohlenz, J., Dumitrescu, A., Zundel, D., Martine, U., Schonberger, W., Koo, E., Weiss, R. E., Cohen, R. N., Kimura, S., Refetoff, S. <strong>Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.</strong> J. Clin. Invest. 109: 469-473, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854318">Pohlenz et al. (2002)</a> found a heterozygous mutation in the TITF1 gene (<a href="#0010">600635.0010</a>). <a href="#20" class="mim-tip-reference" title="Pohlenz, J., Dumitrescu, A., Zundel, D., Martine, U., Schonberger, W., Koo, E., Weiss, R. E., Cohen, R. N., Kimura, S., Refetoff, S. <strong>Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.</strong> J. Clin. Invest. 109: 469-473, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854318">Pohlenz et al. (2002)</a> concluded that haploinsufficiency of the TITF1 gene results in a predominantly neurologic phenotype and secondary hyperthyrotropinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854318" 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 5 unrelated patients with variable degrees of congenital hypothyroidism, choreoathetosis, muscular hypotonia, and pulmonary problems, <a href="#18" class="mim-tip-reference" title="Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., DeFelice, M., von Deimling, A., van Landeghem, F., DiLauro, R., Gruters, A. <strong>Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.</strong> J. Clin. Invest. 109: 475-480, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854319[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854319">Krude et al. (2002)</a> identified 5 different heterozygous loss-of-function mutations in the TTF1 gene: 1 complete gene deletion, 1 missense mutation, and 3 nonsense mutations (see, e.g., <a href="#0005">600635.0005</a> and <a href="#0006">600635.0006</a>). The association of symptoms in the patients with TTF1 mutations pointed to an important role of the human gene in the development and function of the thyroid, basal ganglia, and lung, as had previously been described in rodents (<a href="#16" class="mim-tip-reference" title="Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M., Gonzalez, F. J. <strong>The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.</strong> Genes Dev. 10: 60-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8557195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8557195</a>] [<a href="https://doi.org/10.1101/gad.10.1.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8557195">Kimura et al., 1996</a>). In 1 of the patients, cytogenetic studies identified an interstitial deletion of chromosomal region 14q11.2-q13.3, including the TTF1 gene. Choreoathetosis and respiratory distress were severe, and pulmonary infections were frequent and severe. Thyroid gland imaging showed hypoplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8557195+11854319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Seidman, J. G., Seidman, C. <strong>Transcription factor haploinsufficiency: when half a loaf is not enough. (Commentary)</strong> J. Clin. Invest. 109: 451-455, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854316</a>] [<a href="https://doi.org/10.1172/JCI15043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854316">Seidman and Seidman (2002)</a> commented on <a href="#20" class="mim-tip-reference" title="Pohlenz, J., Dumitrescu, A., Zundel, D., Martine, U., Schonberger, W., Koo, E., Weiss, R. E., Cohen, R. N., Kimura, S., Refetoff, S. <strong>Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.</strong> J. Clin. Invest. 109: 469-473, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854318">Pohlenz et al. (2002)</a> and <a href="#18" class="mim-tip-reference" title="Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., DeFelice, M., von Deimling, A., van Landeghem, F., DiLauro, R., Gruters, A. <strong>Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.</strong> J. Clin. Invest. 109: 475-480, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854319[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854319">Krude et al. (2002)</a> and noted that haploinsufficiency is often the mechanism by which transcription factor defects cause disease. They discussed the diversity of transcription factor haploinsufficiency disorders and tabulated 32 genes that encode transcription factors and cause disease through haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11854316+11854319+11854318" 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 4 affected members of a German family with choreoathetosis, congenital hypothyroidism, and neonatal respiratory insufficiency, <a href="#2" class="mim-tip-reference" title="Asmus, F., Horber, V., Pohlenz, J., Schwabe, D., Zimprich, A., Munz, M., Schoning, M., Gasser, T. <strong>A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.</strong> Neurology 64: 1952-1954, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955952</a>] [<a href="https://doi.org/10.1212/01.WNL.0000164000.75046.CC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955952">Asmus et al. (2005)</a> identified a heterozygous mutation in the TITF1 gene (<a href="#0008">600635.0008</a>). Two patients had a favorable response to levodopa treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955952" 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 patient with choreoathetosis and congenital hypothyroidism, <a href="#4" class="mim-tip-reference" title="Carre, A., Szinnai, G., Castanet, M., Sura-Trueba, S., Tron, E., Broutin-L'Hermite, I., Barat, P., Goizet, C., Lacombe, D., Moutard, M.-L., Raybaud, C., Raynaud-Ravni, C., Romana, S., Ythier, H., Leger, J., Polak, M. <strong>Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case.</strong> Hum. Molec. Genet. 18: 2266-2276, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19336474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19336474</a>] [<a href="https://doi.org/10.1093/hmg/ddp162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19336474">Carre et al. (2009)</a> identified a de novo heterozygous pro202-to-leu (P202L) mutation in the homeodomain of the NKX2-1 gene. Functional analysis of the P202L mutation revealed loss of transactivation capacity on the human thyroglobulin (TG; <a href="/entry/188450">188450</a>) enhancer/promoter. Deficient transcriptional activity of the P202L mutant was completely rescued by cotransfected PAX8 (<a href="/entry/167415">167415</a>), whereas the synergistic effect was abolished by 2 other missense mutations (L176V and Q210P). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19336474" 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>Nonmedullary Thyroid Cancer</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Ngan, E. S. W., Lang, B. H. H., Liu, T., Shum, C. K. Y., So, M.-T., Lau, D. K. C., Leon, T. Y. Y., Cherny, S. S., Tsai, S. Y., Lo, C.-Y., Khoo, U.-S., Tam, P. K. H., Garcia-Barcelo, M.-M. <strong>A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma.</strong> J. Nat. Cancer Inst. 101: 162-175, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19176457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19176457</a>] [<a href="https://doi.org/10.1093/jnci/djn471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19176457">Ngan et al. (2009)</a> identified 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; <a href="/entry/188550">188550</a>) who had an ala339-to-val (A339V) mutation in the TITF1 gene (<a href="#0012">600635.0012</a>). Three of the 4 patients had more advanced tumors than did the remaining 16 patients. Two of these 4 patients had a positive family history of PTC, and the A339V mutation segregated with the phenotype in these families. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Patients carrying the mutation had a higher incidence of perineural infiltration, but it was not statistically significant. Patients carrying the mutation were also more likely than those without the mutation to have had previous thyroid surgery (50% vs 4.0%, p less than 0.001) and MNG (100% vs 5.3%, p less than 0.001). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19176457" 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="#16" class="mim-tip-reference" title="Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M., Gonzalez, F. J. <strong>The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.</strong> Genes Dev. 10: 60-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8557195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8557195</a>] [<a href="https://doi.org/10.1101/gad.10.1.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8557195">Kimura et al. (1996)</a> used homologous recombination to generate mice lacking the Ttf1 gene, or T/ebp. Heterozygotes developed normally, but homozygous deficient mice were born dead and lacked lung parenchyma. The deficient mice lacked a thyroid gland but had a normal parathyroid. In the brain, multiple defects were found in the ventral region of the forebrain, and the entire pituitary was missing. In situ hybridization analysis showed that the T/ebp gene is expressed in normal thyroid, lung bronchial epithelium, and specific areas of the forebrain during early embryogenesis. <a href="#16" class="mim-tip-reference" title="Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M., Gonzalez, F. J. <strong>The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.</strong> Genes Dev. 10: 60-69, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8557195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8557195</a>] [<a href="https://doi.org/10.1101/gad.10.1.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8557195">Kimura et al. (1996)</a> concluded that the TTF1 gene is essential in the embryonic differentiation of the thyroid, lung, ventral forebrain, and pituitary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8557195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Pohlenz, J., Dumitrescu, A., Zundel, D., Martine, U., Schonberger, W., Koo, E., Weiss, R. E., Cohen, R. N., Kimura, S., Refetoff, S. <strong>Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.</strong> J. Clin. Invest. 109: 469-473, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854318">Pohlenz et al. (2002)</a> found that Ttf1 +/- mice demonstrated poor coordination and increased serum thyrotropin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an Italian mother and daughter with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P. <strong>Mutations in TITF-1 are associated with benign hereditary chorea.</strong> Hum. Molec. Genet. 11: 971-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971878</a>] [<a href="https://doi.org/10.1093/hmg/11.8.971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971878">Breedveld et al. (2002)</a> discovered a 1.2-Mb deletion on chromosome 14q which included the TITF1 gene. Haplotype analysis revealed that the mutant chromosome was derived from the grandmother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971878" 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">rs28936671 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936671;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=rs28936671" 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=rs28936671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4-generation Dutch family with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P. <strong>Mutations in TITF-1 are associated with benign hereditary chorea.</strong> Hum. Molec. Genet. 11: 971-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971878</a>] [<a href="https://doi.org/10.1093/hmg/11.8.971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971878">Breedveld et al. (2002)</a> reported heterozygosity for a 727C-A transversion in the TITF1 gene, which was predicted to result in an arg243-to-ser (R243S) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28936672 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936672;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28936672?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28936672" 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=rs28936672" 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=RCV000009537 OR RCV000282710 OR RCV003236767" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009537, RCV000282710, RCV003236767" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009537...</a>
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<p>In a 4-generation American family with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P. <strong>Mutations in TITF-1 are associated with benign hereditary chorea.</strong> Hum. Molec. Genet. 11: 971-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971878</a>] [<a href="https://doi.org/10.1093/hmg/11.8.971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971878">Breedveld et al. (2002)</a> reported heterozygosity for a 713G-T transversion in the TITF1 gene, which was predicted to result in a trp238-to-leu (W238L) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971878" 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 CHOREA, BENIGN HEREDITARY</strong>
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NKX2-1, 1-BP DEL, 908G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906404 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906404;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=rs387906404" 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=rs387906404" 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=RCV000009538" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009538" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009538</a>
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<p>In a 3-generation British family with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#3" class="mim-tip-reference" title="Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P. <strong>Mutations in TITF-1 are associated with benign hereditary chorea.</strong> Hum. Molec. Genet. 11: 971-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971878</a>] [<a href="https://doi.org/10.1093/hmg/11.8.971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971878">Breedveld et al. (2002)</a> reported heterozygosity for a 908G deletion in the TITF1 gene, which was predicted to result in a frameshift and termination of transcription at codon 380. Seventy-seven amino acids are altered, and the terminal 22 amino acids were predicted to be lacking from the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971878" 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 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
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NKX2-1, VAL45PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852692 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852692;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=rs137852692" 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=rs137852692" 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=RCV000009539" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009539" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009539</a>
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<p>In a 15-year-old patient with choreoathetosis, hypothyroidism, and pulmonary dysfunction (CAHTP; <a href="/entry/610978">610978</a>), <a href="#18" class="mim-tip-reference" title="Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., DeFelice, M., von Deimling, A., van Landeghem, F., DiLauro, R., Gruters, A. <strong>Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.</strong> J. Clin. Invest. 109: 475-480, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854319[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854319">Krude et al. (2002)</a> identified a heterozygous 2626G-T transversion in exon 3 of the TITF1 gene, resulting in a val45-to-phe (V45F) substitution in a highly conserved residue within the DNA binding homeodomain of the protein. The patient had apparent athyreosis on neonatal scintigraphy; a hypoplastic thyroid gland was detected on later ultrasound. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
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NKX2-1, 2-BP INS, 2595GG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776707 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776707;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=rs587776707" 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=rs587776707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009540</a>
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<p>In a 3-year-old boy with choreoathetosis and mild thyroid dysfunction (see <a href="/entry/610978">610978</a>), <a href="#18" class="mim-tip-reference" title="Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., DeFelice, M., von Deimling, A., van Landeghem, F., DiLauro, R., Gruters, A. <strong>Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.</strong> J. Clin. Invest. 109: 475-480, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854319[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854319">Krude et al. (2002)</a> identified a heterozygous 2-bp insertion (2595insGG) in exon 3 of the TITF1 gene, resulting in a frameshift that led to a truncated protein lacking the entire third helix of the homeodomain. The patient was affected predominantly by choreoathetosis and had only mild thyroid dysfunction with elevated thyroid-stimulating hormone (TSH) and normal serum thyroid hormone concentrations. The boy had no respiratory distress, and had had only a few mild pulmonary infections. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854319" 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 CHOREA, BENIGN HEREDITARY</strong>
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NKX2-1, IVS2AS, A-T, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776708 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776708;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=rs587776708" 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=rs587776708" 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=RCV000009541 OR RCV000989204 OR RCV002512944" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009541, RCV000989204, RCV002512944" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009541...</a>
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<p>In affected members of a family segregating autosomal dominant benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#17" class="mim-tip-reference" title="Kleiner-Fisman, G., Rogaeva, E., Halliday, W., Houle, S., Kawarai, T., Sato, C., Medeiros, H., St. George-Hyslop, P. H., Lang, A. E. <strong>Benign hereditary chorea: clinical, genetic, and pathological findings.</strong> Ann. Neurol. 54: 244-247, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12891678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12891678</a>] [<a href="https://doi.org/10.1002/ana.10637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12891678">Kleiner-Fisman et al. (2003)</a> identified a heterozygous -2A-T change in the invariant AG splice acceptor site of intron 2 of the TITF1 gene. The mutation is predicted to lead to an aberrant transcript affecting the sequence of exon 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12891678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
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NKX2-1, GLU175TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852693 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852693;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137852693?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852693" 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=rs137852693" 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=RCV000009542 OR RCV001262792 OR RCV001267148 OR RCV002512945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009542, RCV001262792, RCV001267148, RCV002512945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009542...</a>
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<p>In 4 affected members of a family with autosomal dominant choreoathetosis, congenital hypothyroidism, and pulmonary dysfunction (CAHTP; <a href="/entry/610978">610978</a>), <a href="#2" class="mim-tip-reference" title="Asmus, F., Horber, V., Pohlenz, J., Schwabe, D., Zimprich, A., Munz, M., Schoning, M., Gasser, T. <strong>A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.</strong> Neurology 64: 1952-1954, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955952</a>] [<a href="https://doi.org/10.1212/01.WNL.0000164000.75046.CC" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955952">Asmus et al. (2005)</a> identified a heterozygous 523G-T transversion in exon 3 of the TITF1 gene, resulting in a glu175-to-ter (E175X) substitution. Two patients had a favorable response to levodopa treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CHOREA, BENIGN HEREDITARY</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">rs137852694 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852694;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=rs137852694" 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=rs137852694" 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=RCV000009543 OR RCV000792363" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009543, RCV000792363" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009543...</a>
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<p>In a Portuguese mother and son with benign hereditary chorea (BHC; <a href="/entry/118700">118700</a>), <a href="#5" class="mim-tip-reference" title="Costa, M. C., Costa, C., Silva, A. P., Evangelista, P., Santos, L., Ferro, A., Sequeiros, J., Maciel, P. <strong>Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea.</strong> Neurogenetics 6: 209-215, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16220345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16220345</a>] [<a href="https://doi.org/10.1007/s10048-005-0013-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16220345">Costa et al. (2005)</a> identified a heterozygous 745C-T transition in the TITF1 gene, resulting in a gln249-to-ter (Q249X) substitution at the end of helix III of the homeodomain. The mutation is predicted to yield a protein lacking its 153 C-terminal amino acids, including the entire NK2-specific domain. Brain MRI showed symmetrical foci of hyperintense signals in the basal ganglia of the mother and subtle abnormalities of the cerebellum in the son. Neither patient had evidence of thyroid dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16220345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
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NKX2-1, 1-BP INS, 255G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776709;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=rs587776709" 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=rs587776709" 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=RCV000009544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009544</a>
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<p>In a 6-year-old boy with dyskinesia, neonatal respiratory distress requiring mechanical ventilation, and compensated hypothyroidism (CAHTP; <a href="/entry/610978">610978</a>), <a href="#20" class="mim-tip-reference" title="Pohlenz, J., Dumitrescu, A., Zundel, D., Martine, U., Schonberger, W., Koo, E., Weiss, R. E., Cohen, R. N., Kimura, S., Refetoff, S. <strong>Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.</strong> J. Clin. Invest. 109: 469-473, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854318</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11854318[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI14192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854318">Pohlenz et al. (2002)</a> identified a heterozygous 1-bp insertion (255insG) in the TITF1 gene (<a href="#0009">600635.0009</a>), resulting in a nonsense protein of 407 amino acids, rather than the normal 371. The mutant TITF1 did not bind to its canonic cis element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TITF1. Failure of mutant TITF1 to interfere with binding and transactivation functions of wildtype TITF1 suggested that the syndrome was caused by haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
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NKX2-1, IVS2AS, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776708 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776708;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=rs587776708" 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=rs587776708" 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=RCV000009545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009545</a>
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<p>In 4 affected members of a 3-generation family with autosomal dominant congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis (CAHTP; <a href="/entry/610978">610978</a>), <a href="#8" class="mim-tip-reference" title="Doyle, D. A., Gonzalez, I., Thomas, B., Scavina, M. <strong>Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1.</strong> J. Pediat. 145: 190-193, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15289765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15289765</a>] [<a href="https://doi.org/10.1016/j.jpeds.2004.04.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15289765">Doyle et al. (2004)</a> identified a heterozygous A-to-G transition (376-2A-G) in intron 2 of the TITF1 gene. The mutation was predicted to prevent splicing of exons 2 and 3, resulting in a truncated protein and haploinsufficiency of the gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15289765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Carre, A., Szinnai, G., Castanet, M., Sura-Trueba, S., Tron, E., Broutin-L'Hermite, I., Barat, P., Goizet, C., Lacombe, D., Moutard, M.-L., Raybaud, C., Raynaud-Ravni, C., Romana, S., Ythier, H., Leger, J., Polak, M. <strong>Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case.</strong> Hum. Molec. Genet. 18: 2266-2276, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19336474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19336474</a>] [<a href="https://doi.org/10.1093/hmg/ddp162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19336474">Carre et al. (2009)</a> identified heterozygosity for the 376-2A-G mutation in monozygotic twins. The mutation occurred de novo. One twin showed neonatal respiratory distress, congenital hypothyroidism, developed chronic pulmonary infections, and was diagnosed with choreoathetosis at age 5 years. The other twin showed neonatal respiratory distress and congenital hypothyroidism but had no respiratory problems after the neonatal period and had no neurologic symptoms through age 16 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19336474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 THYROID CANCER, NONMEDULLARY, 1</strong>
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NKX2-1, ALA339VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs537209983 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs537209983;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs537209983?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs537209983" 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=rs537209983" 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=RCV000288431 OR RCV000382830 OR RCV000576900 OR RCV002529031" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000288431, RCV000382830, RCV000576900, RCV002529031" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000288431...</a>
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<p>In 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; <a href="/entry/188550">188550</a>), <a href="#19" class="mim-tip-reference" title="Ngan, E. S. W., Lang, B. H. H., Liu, T., Shum, C. K. Y., So, M.-T., Lau, D. K. C., Leon, T. Y. Y., Cherny, S. S., Tsai, S. Y., Lo, C.-Y., Khoo, U.-S., Tam, P. K. H., Garcia-Barcelo, M.-M. <strong>A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma.</strong> J. Nat. Cancer Inst. 101: 162-175, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19176457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19176457</a>] [<a href="https://doi.org/10.1093/jnci/djn471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19176457">Ngan et al. (2009)</a> identified a C-to-T transition at nucleotide 1016 of the TITF1 gene (1016C-T, NM_003317), resulting in an ala339-to-val (A339V) substitution. Two of these 4 patients had a positive family history of PTC. In the first family, 2 family members with the mutation had a history of MNG followed by PTC, whereas the other 2 sibs who carried the mutation had clinically palpable MNG but no evidence of PTC. In the second family, the proband had a history of MNG before PTC, and the other 2 mutation carriers had MNG. The mutation was not found in unaffected members of either family. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Overexpression of A339V mutant protein in PCCL3 cells was associated with increased cell proliferation compared to overexpression of wildtype, including thyrotropin (see <a href="/entry/188540">188540</a>)-independent growth (average A339V proliferation rate = 134.27%, wildtype rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0-47.7%, p = 0.010). Enhanced STAT3 (<a href="/entry/102582">102582</a>) activation and impaired transcription of the thyroid-specific genes TG (<a href="/entry/188450">188450</a>), TSHR (<a href="/entry/603372">603372</a>), and PAX8 (<a href="/entry/167415">167415</a>) were also observed in response to overexpression of A339V mutant TITF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19176457" 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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Garcia-Barcelo, M., Ganster, R. W., Lui, V. C. H., Leon, T. Y. Y., So, M.-T., Lau, A. M. F., Fu, M., Sham, M.-H., Knight, J., Zannini, M. S., Sham, P. C., Tam, P. K. H.
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[<a href="https://doi.org/10.1093/hmg/ddi015" target="_blank">Full Text</a>]
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Garcia-Barcelo, M.-M., Lau, D. K., Ngan, E. S., Leon, T. Y., Liu, T., So, M., Miao, X., Lui, V. C., Wong, K. K., Ganster, R. W., Cass, D. T., Croaker, G. D. H., Tam, P. K.
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[<a href="https://doi.org/10.1111/j.1469-1809.2007.00384.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07574.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.270.14.8108" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1067/mpd.2000.107111" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.10.1.60" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.10637" target="_blank">Full Text</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Zhu2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, N. L., Li, C., Xiao, J., Minoo, P.
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<strong>NKX2.1 regulates transcription of the gene for human bone morphogenetic protein-4 in lung epithelial cells.</strong>
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Gene 327: 25-36, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14960358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14960358</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14960358" 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.gene.2003.11.013" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 04/19/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 8/31/2015<br>Cassandra L. Kniffin - updated : 6/18/2014<br>Ada Hamosh - updated : 1/29/2013<br>Ada Hamosh - updated : 7/8/2011<br>George E. Tiller - updated : 3/3/2010<br>Ada Hamosh - updated : 4/24/2008<br>Carol A. Bocchini - updated : 2/7/2008<br>Marla J. F. O'Neill - updated : 12/14/2007<br>Cassandra L. Kniffin - updated : 4/26/2007<br>John A. Phillips, III - updated : 4/3/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>Cassandra L. Kniffin - updated : 11/22/2005<br>Patricia A. Hartz - updated : 2/28/2005<br>Patricia A. Hartz - updated : 3/24/2004<br>Cassandra L. Kniffin - updated : 12/24/2003<br>Victor A. McKusick - updated : 7/10/2003<br>George E. Tiller - updated : 12/6/2002<br>Paul J. Converse - updated : 1/9/2002
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 8/3/1995
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/03/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/02/2022<br>carol : 08/24/2021<br>mgross : 04/19/2021<br>carol : 03/09/2018<br>alopez : 03/08/2018<br>alopez : 10/17/2016<br>alopez : 09/01/2015<br>alopez : 8/31/2015<br>mcolton : 8/26/2015<br>carol : 6/19/2014<br>mcolton : 6/19/2014<br>ckniffin : 6/18/2014<br>alopez : 1/29/2013<br>terry : 1/29/2013<br>alopez : 7/8/2011<br>alopez : 7/8/2011<br>terry : 7/8/2011<br>wwang : 3/12/2010<br>terry : 3/3/2010<br>wwang : 6/17/2009<br>ckniffin : 6/8/2009<br>ckniffin : 6/8/2009<br>alopez : 5/8/2008<br>terry : 4/24/2008<br>carol : 2/7/2008<br>wwang : 12/14/2007<br>terry : 12/14/2007<br>wwang : 12/6/2007<br>wwang : 5/2/2007<br>ckniffin : 4/26/2007<br>alopez : 4/3/2006<br>wwang : 3/14/2006<br>ckniffin : 3/2/2006<br>carol : 2/13/2006<br>mgross : 2/3/2006<br>terry : 1/27/2006<br>wwang : 12/7/2005<br>ckniffin : 11/22/2005<br>mgross : 2/28/2005<br>mgross : 4/12/2004<br>mgross : 4/12/2004<br>terry : 3/24/2004<br>terry : 3/18/2004<br>joanna : 3/17/2004<br>carol : 12/29/2003<br>ckniffin : 12/24/2003<br>tkritzer : 8/1/2003<br>tkritzer : 7/31/2003<br>terry : 7/10/2003<br>cwells : 12/6/2002<br>mgross : 1/9/2002<br>carol : 2/25/2000<br>mark : 12/14/1997<br>jenny : 4/4/1997<br>mimadm : 11/3/1995<br>mark : 9/19/1995
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600635
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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NK2 HOMEOBOX 1; NKX2-1
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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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<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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THYROID TRANSCRIPTION FACTOR 1; TITF1<br />
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TTF1<br />
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THYROID NUCLEAR FACTOR<br />
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NK2, DROSOPHILA, HOMOLOG OF, A; NKX2A<br />
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NK2.1, MOUSE, HOMOLOG OF<br />
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THYROID-SPECIFIC ENHANCER-BINDING PROTEIN; TEBP
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NKX2-1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230306001;
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</span>
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</p>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 14q13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:36,516,397-36,520,232 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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14q13.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Thyroid cancer, nonmedullary, 1}
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</span>
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</td>
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<td>
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<span class="mim-font">
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188550
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Chorea, hereditary benign
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</span>
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</td>
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<td>
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<span class="mim-font">
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118700
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Choreoathetosis, hypothyroidism, and neonatal respiratory distress
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</span>
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</td>
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<td>
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<span class="mim-font">
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610978
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NKX2-1 gene encodes a transcription factor that is expressed during early development of thyroid, lung, and forebrain regions, particularly the basal ganglia and hypothalamus (summary by Thorwarth et al., 2014). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The protein referred to as thyroid transcription factor-1 (TTF1) by Guazzi et al. (1990) is a 38-kD nuclear protein that mediates thyroid-specific gene transcription. Guazzi et al. (1990) purified the protein from calf thyroids, obtained partial amino acid sequence and cloned the cDNA from a calf thyroid cDNA library using degenerate primers based on the peptide data. The human gene was obtained by Ikeda et al. (1995) and contains a homeobox domain and a 17-amino acid motif characteristic of the NKX2 family of transcription factors. TTF1 activates thyroglobulin (TG; 188450) and thyroperoxidase (TPO; 606765) gene transcription in thyroid adenocarcinomas and is expressed in epithelial cells of the rat thyroid. TTF1 also activates transcription of human surfactant protein B (SFTPB; 178640) in the lung. </p><p>Ikeda et al. (1995) screened a human genomic DNA cosmid library with the rat TTF1 cDNA. A subclone from the cosmid containing the gene was obtained and sequenced. The predicted 371-amino acid protein is 98% identical to the rat sequence. The predominant 2.4-kb RNA was shown to be expressed in pulmonary adenocarcinoma cells in addition to thyroid gland epithelium and the lung. TTF1 protein was detected in fetal lung as early as the eleventh week of gestation and localized in the nuclei of epithelial cells of the developing airways. After birth, expression was seen in type II epithelial cells in the alveoli and in some bronchiolar epithelial cells. When the 5-prime flanking region of the gene was placed in front of a luciferase reporter construct, activity could be measured in pulmonary adenocarcinoma cells. </p><p>Hamdan et al. (1998) isolated several NKX2.1 cDNAs from human lung, which they grouped into 4 distinct classes. All the cDNAs but one encode a protein identical to that reported by Ikeda et al. (1995). The remaining cDNA encodes a putative 402-amino acid protein with an N-terminal extension. Cell-free translation of a transcript encoding the longer protein resulted in polypeptides with apparent molecular masses of 44, 40, and 38 kD by SDS-PAGE. Translation of a transcript encoding the shorter protein resulted in polypeptides of 40 and 38 kD. Hamdan et al. (1998) hypothesized that the different polypeptides result from the use of alternate ATG codons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Family</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>Holland et al. (2007) stated that the NKX2-1 and NKX2-4 (607808) genes are collectively orthologous to Drosophila scro and comprise the Nk2.1 gene family. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Both TTF1 and PAX8 (167415) are thyroid-specific transcription factors that preferentially bind to the thyroglobulin and thyroperoxidase promoters, respectively (Acebron et al., 1995). </p><p>Using yeast 2-hybrid analysis, Yang et al. (2001) showed that BR22 (CCDC59; 619280) interacted with TTF1, and in vitro binding assays with purified recombinant proteins confirmed direct interaction. BR22 and TTF1 formed a complex in transfected HEK293 cells and acted synergistically to increase transactivation activity of the human surfactant protein B (SPB, or SFTPB; 178640) promoter. </p><p>Using immunoprecipitation analysis, Yang et al. (2003) showed that endogenous TAP26 and TTF1 interacted and formed a complex in H441 human lung epithelial cells. </p><p>Using chromatin immunoprecipitation analysis, Yang et al. (2006) identified TAP26 as a coactivator with TTF1 on both the SPB and SPC (SFTPC; 178620) promoter complexes. The TTF1/TAP26 complex stimulated both SPB and SPC promoter activities in H441 cells in a dose-dependent manner. TAP26 alone induced SPB promoter activity, but not SPC promoter activity, in H441 cells. However, in mouse lung MLE12 cells, the TTF1/TAP26 complex or TAP26 alone stimulated only SPB promoter activity, but not SPC promoter activity. The findings indicated that the mechanism for response of the SPC promoter to the complex was different from that of the SPB promoter, and that neither TTF1 nor TAP26 was the limiting factor for the SPC promoter in MLE12 cells. RT-PCR analysis showed that expression of TTF1 and TAP26 was lower in H441 cells compared with MLE12 cells, suggesting that TTF1/TAP26 complex-activated SPC promoter activity was already optimized in MLE12 cells, but not in H441 cells. In addition, SPC promoter stimulation by the TTF1/TAP26 complex in MLE12 cells required TTF1-binding sites T4 and T5 in the proximal region of the SPC promoter. </p><p>Zhu et al. (2004) presented evidence that mouse Titf1, which they called Nkx2.1, is a potential upstream regulator of Bmp4 (112262) expression in lung. Titf1 and Bmp4 were coexpressed in developing mouse lungs. Using EMSA and cotransfection assays in mammalian lung epithelial cells, Zhu et al. (2004) identified functional cis-active Titf1 response elements in both Bmp4 promoter regions. </p><p>Dentice et al. (2005) determined that Titf1 directly controls expression of the pendrin gene (SLC26A4; 605646) in rat thyroid. </p><p>To gain insight into human thyroid development and thyroid dysgenesis-associated malformations, Trueba et al. (2005) studied the expression patterns of the PAX8, TITF1, and FOXE1 (602617) genes during human development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. The expression patterns of these genes in human show some differences from those reported in the mouse; Pax8, Titf1, and Foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. The authors concluded that the expression patterns of these 3 genes correlate well with the phenotypes observed in patients carrying mutations of the corresponding gene. </p><p>Garcia-Barcelo et al. (2005) localized TITF1 to the myenteric and submucosa plexuses in adult human colon and to the mesenchyme of embryonic stomach, where it colocalized with RET (164761). Expression of TITF1 activated RET transcription via a predicted TITF1-binding site in the RET promoter region. </p><p>Weir et al. (2007) reported a large-scale project to characterize copy number alterations in primary lung adenocarcinomas. By analysis of 371 tumors using dense single-nucleotide polymorphism arrays, Weir et al. (2007) identified 57 significantly recurrent events. Weir et al. (2007) found that 26 of 39 autosomal chromosome arms showed consistent large-scale copy number gain or loss, of which only a handful had been linked to a specific gene. They also identified 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only 6 of these focal events were associated with mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, was found in about 12% of samples. On the basis of genomic and functional analyses, Weir et al. (2007) identified NKX2-1, which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate protooncogene involved in a significant fraction of lung adenocarcinomas. </p><p>Taniguchi et al. (2013) followed the development trajectory of chandelier cells, the most distinct interneurons that innervate the axon initial segment of pyramidal neurons and control action potential initiation. Chandelier cells mainly derive from the ventral germinal zone of the lateral ventricle during late gestation and require the homeodomain protein Nkx2.1 for their specification. They migrate with stereotyped routes, and schedule and achieve specific laminar distribution in the cortex. Taniguchi et al. (2013) concluded that the developmental specification of this bona fide interneuron type likely contributes to the assembly of a cortical circuit motif. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Ikeda et al. (1995) determined that the TITF1 gene spans approximately 3.3 kb and contains 2 exons. </p><p>Hamdan et al. (1998) determined that the TITF1 gene contains 3 exons. They identified 2 regions that mediate basal promoter activity in lung epithelial cells, one within the first intron, and the other 5-prime to the first exon. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Guazzi et al. (1990) mapped the TITF1 gene by in situ hybridization to mouse chromosome 12C1-C3 and in humans to chromosome 14q12-q21 with most of the grains localized to 14q13. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</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>Winslow et al. (2011) modeled human lung adenocarcinoma, which frequently harbors activating point mutations in KRAS (190070) and inactivation of the p53 (191170) pathway, using conditional alleles in mice. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma development. Although tumors are initiated synchronously by defined genetic alterations, only a subset becomes malignant, indicating that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed Winslow et al. (2011) to distinguish metastatic from nonmetastatic tumors and determine the gene expression alterations that distinguish these tumor types. Cross-species analysis identified the NK2-related homeobox transcription factor Nkx2-1 as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly differentiated tumors. Gain- and loss-of-function experiments in cells derived from metastatic and nonmetastatic tumors demonstrated that Nkx2-1 controls tumor differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumors at defined developmental stages, and functional complementation experiments indicated that Nkx2-1 constrains tumors in part by repressing the embryonically restricted chromatin regulator Hmga2 (600698). Whereas focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas had focused attention on its oncogenic function, Winslow et al. (2011) stated that their data specifically linked Nkx2-1 downregulation to loss of differentiation, enhanced tumor seeding ability, and increased metastatic proclivity. Winslow et al. (2011) concluded that the oncogenic and suppressive functions of Nkx2-1 in the same tumor type substantiate its role as a dual function lineage factor. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Acebron et al. (1995) reported 3 sibs, a woman and 2 men, with congenital hypothyroid goiter due to defective thyroglobulin synthesis. In the sister, Northern blot analysis, RT-PCR, and electrophoretic mobility shift assays demonstrated virtual absence of TTF1 expression. She had normal levels of PAX8 mRNA and thyroperoxidase mRNA but very low levels of thyroglobulin mRNA. Acebron et al. (1995) stated that this was the first reported evidence of congenital goiter with thyroglobulin synthesis defect due to low expression of TTF1. The parents were unaffected and were not known to be related. </p><p>In 172 sporadic Chinese patients with Hirschsprung disease (HSCR; 142623), Garcia-Barcelo et al. (2005) identified HSCR-associated RET (164761) promoter SNPs that were highly correlated with disease. They determined that the promoter SNPs overlapped a predicted cis-acting TITF1-binding site. Functional analysis demonstrated that the HSCR-associated alleles decreased RET transcription. TITF1 expression activated transcription from the RET promoter, and TITF1-activated RET transcription was reduced by the HSCR-associated SNPs. The authors identified a Chinese patient with HSCR who was heterozygous for a gly322-to-ser (G322S) mutation in the TITF1 gene. The patient did not harbor a mutation in any of the known HSCR-associated genes. Mutant TITF1 specifically decreased the function of the TITF1 5E isoform when assessed on the HSCR-associated RET haplotype. </p><p>Garcia-Barcelo et al. (2007) analyzed the TITF1 gene in an additional 102 Chinese and 70 Australian Caucasian HSCR patients and identified a met3-to-leu (M3L) mutation in 2 of the Australian patients that was not found in 194 Chinese and 60 Caucasian unrelated controls. In vitro functional studies showed that M3L completely abolished the activation of RET by TITF1, irrespective of the HSCR-associated haplotype in the RET promoter. </p><p><strong><em>Benign Hereditary Chorea</em></strong></p><p>
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|
In affected members of a family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) identified a heterozygous 1.2-Mb deletion including the TITF1 gene. The authors also reported other BHC families with heterozygous point mutations in the TITF1 gene (see, e.g., 600635.0001-600635.0004). </p><p><strong><em>Choreoathetosis and Congenital Hypothyroidism with or without Pulmonary Dysfunction</em></strong></p><p>
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|
Devriendt et al. (1998) identified deletion of the TTF1 gene in an infant with choreoathetosis and congenital hypothyroidism with pulmonary dysfunction (CAHTP; 610978). The infant presented with respiratory failure, hypotonia, and truncal ataxia. Iwatani et al. (2000) reported deletion of the gene in 2 sibs with hypothyroidism and respiratory failure. </p><p>In a 6-year-old boy with dyskinesia, neonatal respiratory distress, and compensated hypothyroidism, Pohlenz et al. (2002) found a heterozygous mutation in the TITF1 gene (600635.0010). Pohlenz et al. (2002) concluded that haploinsufficiency of the TITF1 gene results in a predominantly neurologic phenotype and secondary hyperthyrotropinemia. </p><p>In 5 unrelated patients with variable degrees of congenital hypothyroidism, choreoathetosis, muscular hypotonia, and pulmonary problems, Krude et al. (2002) identified 5 different heterozygous loss-of-function mutations in the TTF1 gene: 1 complete gene deletion, 1 missense mutation, and 3 nonsense mutations (see, e.g., 600635.0005 and 600635.0006). The association of symptoms in the patients with TTF1 mutations pointed to an important role of the human gene in the development and function of the thyroid, basal ganglia, and lung, as had previously been described in rodents (Kimura et al., 1996). In 1 of the patients, cytogenetic studies identified an interstitial deletion of chromosomal region 14q11.2-q13.3, including the TTF1 gene. Choreoathetosis and respiratory distress were severe, and pulmonary infections were frequent and severe. Thyroid gland imaging showed hypoplasia. </p><p>Seidman and Seidman (2002) commented on Pohlenz et al. (2002) and Krude et al. (2002) and noted that haploinsufficiency is often the mechanism by which transcription factor defects cause disease. They discussed the diversity of transcription factor haploinsufficiency disorders and tabulated 32 genes that encode transcription factors and cause disease through haploinsufficiency. </p><p>In 4 affected members of a German family with choreoathetosis, congenital hypothyroidism, and neonatal respiratory insufficiency, Asmus et al. (2005) identified a heterozygous mutation in the TITF1 gene (600635.0008). Two patients had a favorable response to levodopa treatment. </p><p>In a patient with choreoathetosis and congenital hypothyroidism, Carre et al. (2009) identified a de novo heterozygous pro202-to-leu (P202L) mutation in the homeodomain of the NKX2-1 gene. Functional analysis of the P202L mutation revealed loss of transactivation capacity on the human thyroglobulin (TG; 188450) enhancer/promoter. Deficient transcriptional activity of the P202L mutant was completely rescued by cotransfected PAX8 (167415), whereas the synergistic effect was abolished by 2 other missense mutations (L176V and Q210P). </p><p><strong><em>Nonmedullary Thyroid Cancer</em></strong></p><p>
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|
Ngan et al. (2009) identified 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; 188550) who had an ala339-to-val (A339V) mutation in the TITF1 gene (600635.0012). Three of the 4 patients had more advanced tumors than did the remaining 16 patients. Two of these 4 patients had a positive family history of PTC, and the A339V mutation segregated with the phenotype in these families. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Patients carrying the mutation had a higher incidence of perineural infiltration, but it was not statistically significant. Patients carrying the mutation were also more likely than those without the mutation to have had previous thyroid surgery (50% vs 4.0%, p less than 0.001) and MNG (100% vs 5.3%, p less than 0.001). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kimura et al. (1996) used homologous recombination to generate mice lacking the Ttf1 gene, or T/ebp. Heterozygotes developed normally, but homozygous deficient mice were born dead and lacked lung parenchyma. The deficient mice lacked a thyroid gland but had a normal parathyroid. In the brain, multiple defects were found in the ventral region of the forebrain, and the entire pituitary was missing. In situ hybridization analysis showed that the T/ebp gene is expressed in normal thyroid, lung bronchial epithelium, and specific areas of the forebrain during early embryogenesis. Kimura et al. (1996) concluded that the TTF1 gene is essential in the embryonic differentiation of the thyroid, lung, ventral forebrain, and pituitary. </p><p>Pohlenz et al. (2002) found that Ttf1 +/- mice demonstrated poor coordination and increased serum thyrotropin. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 CHOREA, BENIGN HEREDITARY</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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NKX2-1, 1.2-MB DEL
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<br />
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ClinVar: RCV000009535
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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 Italian mother and daughter with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) discovered a 1.2-Mb deletion on chromosome 14q which included the TITF1 gene. Haplotype analysis revealed that the mutant chromosome was derived from the grandmother. </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>.0002 CHOREA, BENIGN HEREDITARY</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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NKX2-1, ARG243SER
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<br />
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|
|
SNP: rs28936671,
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ClinVar: RCV000009536
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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 4-generation Dutch family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 727C-A transversion in the TITF1 gene, which was predicted to result in an arg243-to-ser (R243S) substitution. </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>.0003 CHOREA, BENIGN HEREDITARY</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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|
NKX2-1, TRP238LEU
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<br />
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|
|
SNP: rs28936672,
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|
|
gnomAD: rs28936672,
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|
|
ClinVar: RCV000009537, RCV000282710, RCV003236767
|
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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 4-generation American family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 713G-T transversion in the TITF1 gene, which was predicted to result in a trp238-to-leu (W238L) substitution. </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>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CHOREA, BENIGN HEREDITARY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
NKX2-1, 1-BP DEL, 908G
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|
|
|
<br />
|
|
|
|
SNP: rs387906404,
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|
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|
|
ClinVar: RCV000009538
|
|
|
|
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|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-generation British family with benign hereditary chorea (BHC; 118700), Breedveld et al. (2002) reported heterozygosity for a 908G deletion in the TITF1 gene, which was predicted to result in a frameshift and termination of transcription at codon 380. Seventy-seven amino acids are altered, and the terminal 22 amino acids were predicted to be lacking from the mutant protein. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
NKX2-1, VAL45PHE
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<br />
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|
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SNP: rs137852692,
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|
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|
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ClinVar: RCV000009539
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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 15-year-old patient with choreoathetosis, hypothyroidism, and pulmonary dysfunction (CAHTP; 610978), Krude et al. (2002) identified a heterozygous 2626G-T transversion in exon 3 of the TITF1 gene, resulting in a val45-to-phe (V45F) substitution in a highly conserved residue within the DNA binding homeodomain of the protein. The patient had apparent athyreosis on neonatal scintigraphy; a hypoplastic thyroid gland was detected on later ultrasound. </p>
|
|
</span>
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|
</div>
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|
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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 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
NKX2-1, 2-BP INS, 2595GG
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<br />
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|
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SNP: rs587776707,
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|
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|
|
|
|
|
ClinVar: RCV000009540
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old boy with choreoathetosis and mild thyroid dysfunction (see 610978), Krude et al. (2002) identified a heterozygous 2-bp insertion (2595insGG) in exon 3 of the TITF1 gene, resulting in a frameshift that led to a truncated protein lacking the entire third helix of the homeodomain. The patient was affected predominantly by choreoathetosis and had only mild thyroid dysfunction with elevated thyroid-stimulating hormone (TSH) and normal serum thyroid hormone concentrations. The boy had no respiratory distress, and had had only a few mild pulmonary infections. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CHOREA, BENIGN HEREDITARY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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NKX2-1, IVS2AS, A-T, -2
|
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<br />
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|
|
SNP: rs587776708,
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|
|
|
|
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ClinVar: RCV000009541, RCV000989204, RCV002512944
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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 affected members of a family segregating autosomal dominant benign hereditary chorea (BHC; 118700), Kleiner-Fisman et al. (2003) identified a heterozygous -2A-T change in the invariant AG splice acceptor site of intron 2 of the TITF1 gene. The mutation is predicted to lead to an aberrant transcript affecting the sequence of exon 3. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</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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NKX2-1, GLU175TER
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<br />
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SNP: rs137852693,
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gnomAD: rs137852693,
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ClinVar: RCV000009542, RCV001262792, RCV001267148, RCV002512945
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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 4 affected members of a family with autosomal dominant choreoathetosis, congenital hypothyroidism, and pulmonary dysfunction (CAHTP; 610978), Asmus et al. (2005) identified a heterozygous 523G-T transversion in exon 3 of the TITF1 gene, resulting in a glu175-to-ter (E175X) substitution. Two patients had a favorable response to levodopa treatment. </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>.0009 CHOREA, BENIGN HEREDITARY</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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NKX2-1, GLN249TER
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<br />
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SNP: rs137852694,
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ClinVar: RCV000009543, RCV000792363
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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 Portuguese mother and son with benign hereditary chorea (BHC; 118700), Costa et al. (2005) identified a heterozygous 745C-T transition in the TITF1 gene, resulting in a gln249-to-ter (Q249X) substitution at the end of helix III of the homeodomain. The mutation is predicted to yield a protein lacking its 153 C-terminal amino acids, including the entire NK2-specific domain. Brain MRI showed symmetrical foci of hyperintense signals in the basal ganglia of the mother and subtle abnormalities of the cerebellum in the son. Neither patient had evidence of thyroid dysfunction. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</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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NKX2-1, 1-BP INS, 255G
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<br />
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SNP: rs587776709,
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ClinVar: RCV000009544
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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-year-old boy with dyskinesia, neonatal respiratory distress requiring mechanical ventilation, and compensated hypothyroidism (CAHTP; 610978), Pohlenz et al. (2002) identified a heterozygous 1-bp insertion (255insG) in the TITF1 gene (600635.0009), resulting in a nonsense protein of 407 amino acids, rather than the normal 371. The mutant TITF1 did not bind to its canonic cis element or transactivate a reporter gene driven by the thyroglobulin promoter, a natural target of TITF1. Failure of mutant TITF1 to interfere with binding and transactivation functions of wildtype TITF1 suggested that the syndrome was caused by 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">
|
|
<strong>.0011 CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION</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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NKX2-1, IVS2AS, A-G, -2
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<br />
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SNP: rs587776708,
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ClinVar: RCV000009545
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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 4 affected members of a 3-generation family with autosomal dominant congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis (CAHTP; 610978), Doyle et al. (2004) identified a heterozygous A-to-G transition (376-2A-G) in intron 2 of the TITF1 gene. The mutation was predicted to prevent splicing of exons 2 and 3, resulting in a truncated protein and haploinsufficiency of the gene product. </p><p>Carre et al. (2009) identified heterozygosity for the 376-2A-G mutation in monozygotic twins. The mutation occurred de novo. One twin showed neonatal respiratory distress, congenital hypothyroidism, developed chronic pulmonary infections, and was diagnosed with choreoathetosis at age 5 years. The other twin showed neonatal respiratory distress and congenital hypothyroidism but had no respiratory problems after the neonatal period and had no neurologic symptoms through age 16 years. </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>.0012 THYROID CANCER, NONMEDULLARY, 1</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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NKX2-1, ALA339VAL
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<br />
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SNP: rs537209983,
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gnomAD: rs537209983,
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ClinVar: RCV000288431, RCV000382830, RCV000576900, RCV002529031
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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 4 of 20 unrelated patients with multinodular goiter (MNG)/papillary thyroid carcinoma (PTC) (NMTC1; 188550), Ngan et al. (2009) identified a C-to-T transition at nucleotide 1016 of the TITF1 gene (1016C-T, NM_003317), resulting in an ala339-to-val (A339V) substitution. Two of these 4 patients had a positive family history of PTC. In the first family, 2 family members with the mutation had a history of MNG followed by PTC, whereas the other 2 sibs who carried the mutation had clinically palpable MNG but no evidence of PTC. In the second family, the proband had a history of MNG before PTC, and the other 2 mutation carriers had MNG. The mutation was not found in unaffected members of either family. The mutation was not found among 349 healthy control subjects or among 284 PTC patients who had no history of MNG. Overexpression of A339V mutant protein in PCCL3 cells was associated with increased cell proliferation compared to overexpression of wildtype, including thyrotropin (see 188540)-independent growth (average A339V proliferation rate = 134.27%, wildtype rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0-47.7%, p = 0.010). Enhanced STAT3 (102582) activation and impaired transcription of the thyroid-specific genes TG (188450), TSHR (603372), and PAX8 (167415) were also observed in response to overexpression of A339V mutant TITF1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Acebron, A., Aza-Blanc, P., Rossi, D. L., Lamas, L., Santisteban, P.
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<strong>Congenital human thyroglobulin defect due to low expression of the thyroid-specific transcription factor TTF-1.</strong>
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<li>
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<p class="mim-text-font">
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Asmus, F., Horber, V., Pohlenz, J., Schwabe, D., Zimprich, A., Munz, M., Schoning, M., Gasser, T.
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<strong>A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.</strong>
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Breedveld, G. J., van Dongen, J. W. F., Danesino, C., Guala, A., Percy, A. K., Dure, L. S., Harper, P., Lazarou, L. P., van der Linde, H., Joosse, M., Gruters, A., MacDonald, M. E., de Vries, B. B. A., Arts, W. F. M., Oostra, B. A., Krude, H., Heutink, P.
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Carre, A., Szinnai, G., Castanet, M., Sura-Trueba, S., Tron, E., Broutin-L'Hermite, I., Barat, P., Goizet, C., Lacombe, D., Moutard, M.-L., Raybaud, C., Raynaud-Ravni, C., Romana, S., Ythier, H., Leger, J., Polak, M.
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Costa, M. C., Costa, C., Silva, A. P., Evangelista, P., Santos, L., Ferro, A., Sequeiros, J., Maciel, P.
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<strong>Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea.</strong>
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<p class="mim-text-font">
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Dentice, M., Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., Di Lauro, R., Rossi, G., Fenzi, G., Salvatore, D.
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<strong>Pendrin is a novel in vivo downstream target gene of the TTF-1/Nkx-2.1 homeodomain transcription factor in differentiated thyroid cells.</strong>
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Devriendt, K., Vanhole, C., Matthijs, G., de Zegher, F.
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<strong>Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. (Letter)</strong>
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<p class="mim-text-font">
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Doyle, D. A., Gonzalez, I., Thomas, B., Scavina, M.
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<p class="mim-text-font">
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Garcia-Barcelo, M., Ganster, R. W., Lui, V. C. H., Leon, T. Y. Y., So, M.-T., Lau, A. M. F., Fu, M., Sham, M.-H., Knight, J., Zannini, M. S., Sham, P. C., Tam, P. K. H.
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<strong>TTF-1 and RET promoter SNPs: regulation of RET transcription in Hirschsprung's disease.</strong>
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<p class="mim-text-font">
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<li>
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<p class="mim-text-font">
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Guazzi, S., Price, M., De Felice, M., Damante, G., Mattei, M.-G., Di Lauro, R.
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<strong>Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity.</strong>
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EMBO J. 9: 3631-3639, 1990.
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[PubMed: 1976511]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1990.tb07574.x]
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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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Hamdan, H., Liu, H., Li, C., Jones, C., Lee, M., deLemos, R., Minoo, P.
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<strong>Structure of the human Nkx2.1 gene.</strong>
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Biochim. Biophys. Acta 1396: 336-348, 1998.
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[PubMed: 9545595]
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</p>
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<li>
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<p class="mim-text-font">
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Holland, P. W. H., Booth, H. A. F., Bruford, E. A.
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<strong>Classification and nomenclature of all human homeobox genes.</strong>
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BMC Biol. 5: 47, 2007. Note: Electronic Article.
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[PubMed: 17963489]
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[Full Text: https://doi.org/10.1186/1741-7007-5-47]
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</p>
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<li>
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<p class="mim-text-font">
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Ikeda, K., Clark, J. C., Shaw-White, J. R., Stahlman, M. T., Boutell, C. J., Whitsett, J. A.
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<strong>Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.</strong>
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J. Biol. Chem. 270: 8108-8114, 1995.
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[PubMed: 7713914]
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[Full Text: https://doi.org/10.1074/jbc.270.14.8108]
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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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|
Iwatani, N., Mabe, H., Devriendt, K., Kodama, M., Miike, T.
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<strong>Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure.</strong>
|
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J. Pediat. 137: 272-276, 2000.
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[PubMed: 10931427]
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[Full Text: https://doi.org/10.1067/mpd.2000.107111]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M., Gonzalez, F. J.
|
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<strong>The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.</strong>
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Genes Dev. 10: 60-69, 1996.
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|
[PubMed: 8557195]
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[Full Text: https://doi.org/10.1101/gad.10.1.60]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kleiner-Fisman, G., Rogaeva, E., Halliday, W., Houle, S., Kawarai, T., Sato, C., Medeiros, H., St. George-Hyslop, P. H., Lang, A. E.
|
|
<strong>Benign hereditary chorea: clinical, genetic, and pathological findings.</strong>
|
|
Ann. Neurol. 54: 244-247, 2003.
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|
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|
|
[PubMed: 12891678]
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|
[Full Text: https://doi.org/10.1002/ana.10637]
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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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Krude, H., Schutz, B., Biebermann, H., von Moers, A., Schnabel, D., Neitzel, H., Tonnies, H., Weise, D., Lafferty, A., Schwarz, S., DeFelice, M., von Deimling, A., van Landeghem, F., DiLauro, R., Gruters, A.
|
|
<strong>Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.</strong>
|
|
J. Clin. Invest. 109: 475-480, 2002.
|
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