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- *602272 - TRANSCRIPTION FACTOR 4; TCF4
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602272</span>
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<br />
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<strong>Table of Contents</strong>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/602272">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div 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=ENSG00000196628;t=ENST00000354452" 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=6925" 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=602272" 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=ENSG00000196628;t=ENST00000354452" 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_001083962,NM_001243226,NM_001243227,NM_001243228,NM_001243230,NM_001243231,NM_001243232,NM_001243233,NM_001243234,NM_001243235,NM_001243236,NM_001306207,NM_001306208,NM_001330604,NM_001330605,NM_001348211,NM_001348212,NM_001348213,NM_001348214,NM_001348215,NM_001348216,NM_001348217,NM_001348218,NM_001348219,NM_001348220,NM_001369567,NM_001369568,NM_001369569,NM_001369570,NM_001369571,NM_001369572,NM_001369573,NM_001369574,NM_001369575,NM_001369576,NM_001369577,NM_001369578,NM_001369579,NM_001369580,NM_001369581,NM_001369582,NM_001369583,NM_001369584,NM_001369585,NM_001369586,NM_003199" 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_001083962" 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=602272" 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=03780&isoform_id=03780_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/TCF4" 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/338013,338015,338017,1184243,2570271,3915747,4507399,62089062,115527739,115527990,119583421,119583422,119583423,119583424,119583425,119583426,119583427,119583428,145312267,193783734,193787771,193788488,194374025,194390174,221042570,221043274,221043480,221045718,340522955,340522957,340522959,340522961,340522963,340522965,340522967,340522969,340522971,340522973,340522975,340522977,340522979,340522981,340522983,340522985,340522987,340522989,340522991,340522993,340522995,340522997,342672061,342672063,342672065,342672067,342672069,342672071,342672073,342672075,342672077,597709768,807201174,807201180,1060604592,1060604607,1134377766,1134377768,1134612220,1134612236,1134612248,1134612258,1143076998,1143077000,1143077002,1143077004,1613451997,1613451999,1613452002,1613452004,1613452006,1613452008,1613452010,1613452012,1613452014,1613452016,1613452018,1613452020,1613452022,1613452024,1613452026,1678209469,1678209476,1678209481,1678209485,1678209507" 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/P15884" 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=6925" 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=ENSG00000196628;t=ENST00000354452" 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=TCF4" 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=TCF4" 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+6925" 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/TCF4" 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:6925" 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/6925" 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=chr18&hgg_gene=ENST00000354452.8&hgg_start=55222185&hgg_end=55635957&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11634" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11634" 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/tcf4" 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=602272[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=602272[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/TCF4/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/ENSG00000196628" 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=TCF4" 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=TCF4" 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=TCF4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/TCF4" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TCF4&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/PA164742621" 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:11634" 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/FBgn0267821.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:98506" 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/TCF4#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:98506" 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/6925/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=6925" 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=WBGene00001949;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-090814-1" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:602272" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=TCF4&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> 702344008<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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602272
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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TRANSCRIPTION FACTOR 4; TCF4
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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IMMUNOGLOBULIN TRANSCRIPTION FACTOR 2; ITF2<br />
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SEF2-1B<br />
|
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SEF2<br />
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E2-2
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TCF4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TCF4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/18/199?start=-3&limit=10&highlight=199">18q21.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:55222185-55635957&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'})">18:55,222,185-55,635,957</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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Corneal dystrophy, Fuchs endothelial, 3
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/602272" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602272" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>TCF4 is a broadly expressed basic helix-loop-helix (bHLH) protein that functions as a homodimer or as a heterodimer with other bHLH proteins. These dimers bind DNA at Ephrussi (E) box sequences. Alternative splicing produces numerous N-terminally distinct TCF4 isoforms that differ in their subcellular localization and transactivational capacity (summary by <a href="#20" class="mim-tip-reference" title="Sepp, M., Pruunsild, P., Timmusk, T. <strong>Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.</strong> Hum. Molec. Genet. 21: 2873-2888, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22460224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22460224</a>] [<a href="https://doi.org/10.1093/hmg/dds112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22460224">Sepp et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22460224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Corneliussen, B., Thornell, A., Hallberg, B., Grundstrom, T. <strong>Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers.</strong> J. Virol. 65: 6084-6093, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1681116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1681116</a>] [<a href="https://doi.org/10.1128/JVI.65.11.6084-6093.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1681116">Corneliussen et al. (1991)</a> identified a family of nuclear proteins that bind to a motif of the glucocorticoid response element (GRE) in the enhancer of the murine leukemia virus SL3-3. This motif resembled those found in E boxes. <a href="#4" class="mim-tip-reference" title="Corneliussen, B., Thornell, A., Hallberg, B., Grundstrom, T. <strong>Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers.</strong> J. Virol. 65: 6084-6093, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1681116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1681116</a>] [<a href="https://doi.org/10.1128/JVI.65.11.6084-6093.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1681116">Corneliussen et al. (1991)</a> termed this family SEF2 for 'SL3-3 enhancer factors 2.' They cloned the gene encoding one of these proteins, SEF2-1B, from human thymocytes. <a href="#4" class="mim-tip-reference" title="Corneliussen, B., Thornell, A., Hallberg, B., Grundstrom, T. <strong>Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers.</strong> J. Virol. 65: 6084-6093, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1681116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1681116</a>] [<a href="https://doi.org/10.1128/JVI.65.11.6084-6093.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1681116">Corneliussen et al. (1991)</a> found that the SEF2-1B gene encodes a 667-amino acid polypeptide with homology to other bHLH transcription factors. <a href="#4" class="mim-tip-reference" title="Corneliussen, B., Thornell, A., Hallberg, B., Grundstrom, T. <strong>Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers.</strong> J. Virol. 65: 6084-6093, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1681116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1681116</a>] [<a href="https://doi.org/10.1128/JVI.65.11.6084-6093.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1681116">Corneliussen et al. (1991)</a> found multiple related mRNA species, presumed to be the result of differential splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1681116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Henthorn, P., Kiledjian, M., Kadesch, T. <strong>Two distinct transcription factors that bind the immunoglobulin enhancer mu-E5/kappa-E2 motif.</strong> Science 247: 467-470, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2105528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2105528</a>] [<a href="https://doi.org/10.1126/science.2105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2105528">Henthorn et al. (1990)</a> identified a helix-loop-helix transcription factor that bound to the mu-E5 motif of the immunoglobulin heavy chain enhancer and to the kappa-E2 motif found in the light chain enhancer, and designated it ITF2 for 'immunoglobulin transcription factor 2.' ITF2 encodes a predicted 623-amino acid protein (<a href="#11" class="mim-tip-reference" title="Henthorn, P., McCarrick-Walmsley, R., Kadesch, T. <strong>Sequence of the cDNA encoding ITF-2, a positive-acting transcription factor.</strong> Nucleic Acids Res. 18: 678, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2308860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2308860</a>] [<a href="https://doi.org/10.1093/nar/18.3.678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2308860">Henthorn et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2105528+2308860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Pscherer, A., Dorflinger, U., Kirfel, J., Gawlas, K., Ruschoff, J., Buettner, R., Schule, R. <strong>The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene.</strong> EMBO J. 15: 6680-6690, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978694</a>]" pmid="8978694">Pscherer et al. (1996)</a> isolated the promoter region of human somatostatin receptor-2 (SSTR2; <a href="/entry/182452">182452</a>) and identified a novel initiator element. By screening a mouse brain cDNA expression library, <a href="#18" class="mim-tip-reference" title="Pscherer, A., Dorflinger, U., Kirfel, J., Gawlas, K., Ruschoff, J., Buettner, R., Schule, R. <strong>The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene.</strong> EMBO J. 15: 6680-6690, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978694</a>]" pmid="8978694">Pscherer et al. (1996)</a> isolated a transcription factor, which they termed Sef2, that bound to the E box of the SSTR2 initiator element. Sequencing revealed that this factor was the murine homolog of human SEF2-1B. DNA binding studies demonstrated that the basal transcription factor TFIIB (<a href="/entry/189963">189963</a>) can be tethered to the SSTR2 initiator element through physical interaction with SEF2. Northern blot analysis revealed that SEF2-1B is expressed in human adult and embryonic tissues including heart, brain, placenta, skeletal muscle, and lung. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8978694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 search for polymorphic CTG repeats as candidate genes for bipolar disorder, <a href="#2" class="mim-tip-reference" title="Breschel, T. S., McInnis, M. G., Margolis, R. L., Sirugo, G., Corneliussen, B., Simpson, S. G., McMahon, F. J., MacKinnon, D. F., Xu, J. F., Pleasant, N., Huo, Y., Ashworth, R. G., Grundstrom, C., Grundstrom, T., Kidd, K. K., DePaulo, J. R., Ross, C. A. <strong>A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.</strong> Hum. Molec. Genet. 6: 1855-1863, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302263</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302263">Breschel et al. (1997)</a> screened a genomic human chromosome 18-specific library and identified a 1.6-kb clone with a CTG(24) repeat that mapped to 18q21.1, which they designated CTG18.1 (see <a href="#0007">602272.0007</a>). The expansion was located in an intron of SEF2-1. The repeat was highly polymorphic in both bipolar and control subjects with an observed heterozygosity of 84%. Expansions of up to CTG(2100) were possible but were not associated with an obvious abnormal phenotype. The location of the repeat was determined by radiation hybrid mapping and by linkage analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By database analysis, <a href="#3" class="mim-tip-reference" title="Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G. <strong>Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.</strong> Hum. Molec. Genet. 16: 1488-1494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17478476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17478476</a>] [<a href="https://doi.org/10.1093/hmg/ddm099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17478476">Brockschmidt et al. (2007)</a> identified the TCF4 ortholog in zebrafish. Whole-mount in situ hybridization showed expression of Tcf4 in the developing zebrafish brain. Tcf4 was first expressed in the telencephalic/diencephalic border, with later expression in the dorsal telencephalon and the diencephalon, including the thalamus, ventral thalamus and posterior tuberculum, and in the midbrain tegmentum. Tcf4 was not expressed in the hypothalamus, whereas it showed later expression in the retina and branchial arches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17478476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. <strong>Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.</strong> Hum. Mutat. 30: 669-676, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19235238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19235238</a>] [<a href="https://doi.org/10.1002/humu.20935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19235238">De Pontual et al. (2009)</a> found that TCF4 was highly expressed in the developing human central nervous system, sclerotomal components of the somites, the condensing vertebral body, the limb bud, splanchnopleural mesenchyme, and the gonadal ridge. It was later expressed in various nervous system tissues, thyroid, thymus, kidney, and gonads. In postnatal life, expression was observed in adult lymphocytes, fibroblasts, gut, muscle, and myenteric plexus. Expression was not seen in cardiac muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19235238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Sepp, M., Pruunsild, P., Timmusk, T. <strong>Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.</strong> Hum. Molec. Genet. 21: 2873-2888, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22460224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22460224</a>] [<a href="https://doi.org/10.1093/hmg/dds112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22460224">Sepp et al. (2012)</a> reported that the full-length 671-amino acid TCF4 isoform has an N-terminal transcriptional activation domain (AD1), followed by a nuclear localization signal (NLS), a second transcriptional activation domain (AD2), and a C-terminal bHLH domain that mediates dimerization and E-box binding. Alternative splicing at the 5-prime end results in TCF4 proteins with 18 different N termini. These isoforms may lack AD1 and/or NLS, but all have AD2 and bHLH domains. In addition, some isoforms lack 4 amino acids between the AD2 and bHLH domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22460224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Breschel, T. S., McInnis, M. G., Margolis, R. L., Sirugo, G., Corneliussen, B., Simpson, S. G., McMahon, F. J., MacKinnon, D. F., Xu, J. F., Pleasant, N., Huo, Y., Ashworth, R. G., Grundstrom, C., Grundstrom, T., Kidd, K. K., DePaulo, J. R., Ross, C. A. <strong>A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.</strong> Hum. Molec. Genet. 6: 1855-1863, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302263</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302263">Breschel et al. (1997)</a> showed that the mouse Sef2-1 gene contains 22 exons, with many of the introns more than 10 kb long. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> determined that the human TCF4 gene contains 20 exons (exons 1 and 20 are noncoding), spans 360 kb, and encodes at least 2 isoforms that differ in the presence or absence of 4 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#20" class="mim-tip-reference" title="Sepp, M., Pruunsild, P., Timmusk, T. <strong>Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.</strong> Hum. Molec. Genet. 21: 2873-2888, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22460224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22460224</a>] [<a href="https://doi.org/10.1093/hmg/dds112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22460224">Sepp et al. (2012)</a> reported that the 5-prime end of the TCF4 gene is subject to complex alternative splicing. Exons 10 through 21 are common to all TCF4 transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22460224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#2" class="mim-tip-reference" title="Breschel, T. S., McInnis, M. G., Margolis, R. L., Sirugo, G., Corneliussen, B., Simpson, S. G., McMahon, F. J., MacKinnon, D. F., Xu, J. F., Pleasant, N., Huo, Y., Ashworth, R. G., Grundstrom, C., Grundstrom, T., Kidd, K. K., DePaulo, J. R., Ross, C. A. <strong>A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.</strong> Hum. Molec. Genet. 6: 1855-1863, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302263</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302263">Breschel et al. (1997)</a> mapped a CTG repeat within an intron of the TCF4 gene to chromosome 18q21.1 by genomic sequence analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>DNA binding studies by <a href="#18" class="mim-tip-reference" title="Pscherer, A., Dorflinger, U., Kirfel, J., Gawlas, K., Ruschoff, J., Buettner, R., Schule, R. <strong>The helix-loop-helix transcription factor SEF-2 regulates the activity of a novel initiator element in the promoter of the human somatostatin receptor II gene.</strong> EMBO J. 15: 6680-6690, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8978694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8978694</a>]" pmid="8978694">Pscherer et al. (1996)</a> demonstrated that the basal transcription factor TFIIB (<a href="/entry/189963">189963</a>) could be tethered to the SSTR2 initiator element through physical interaction with SEF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8978694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Dorflinger, U., Pscherer, A., Moser, M., Rummele, P., Schule, R., Buettner, R. <strong>Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.</strong> Molec. Cell. Biol. 19: 3736-3747, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10207097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10207097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10207097[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.19.5.3736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10207097">Dorflinger et al. (1999)</a> showed that Mibp1 (HIVEP2; <a href="/entry/143054">143054</a>) interacted with Sef2 to enhance transcription from the basal Sstr2 promoter in murine brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10207097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Luo, C., Lim, J.-H., Lee, Y., Granter, S. R., Thomas, A., Vazquez, F., Widlund, H. R., Puigserver, P. <strong>A PGC1-alpha-mediated transcriptional axis suppresses melanoma metastasis.</strong> Nature 537: 422-426, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27580028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27580028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27580028[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/nature19347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27580028">Luo et al. (2016)</a> provided data indicating that PGC1-alpha (<a href="/entry/604517">604517</a>) suppresses melanoma (<a href="/entry/155600">155600</a>) metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1-alpha expression inversely correlated with vertical growth in human melanoma specimens. Mechanistically, PGC1-alpha directly increases transcription of ID2 (<a href="/entry/600386">600386</a>), which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 caused downregulation of metastasis-related genes, including integrins that influence invasion and metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27580028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Bipolar Affective Disorder</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Del-Favero, J., Van Gestel, S., Borglum, A. D., Muir, W., Ewald, H., Mors, O., Ivezic, S., Oruc, L., Adolfsson, R., Blackwood, D., Kruse, T., Mendlewicz, J., Schalling, M., Van Broeckhoven, C. <strong>European combined analysis of the CTG18.1 and the ERDA1 CAG/CTG repeats in bipolar disorder.</strong> Europ. J. Hum. Genet. 10: 276-280, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032737</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12032737">Del-Favero et al. (2002)</a> studied the CTG repeat in the third intron of the SEF2-1B gene in a large combined European case-control sample of bipolar affective disorder (<a href="/entry/125480">125480</a>). The sample consisted of 403 patients and 486 controls matched for age, gender, and ethnicity. The patients were consecutively recruited from 5 participating centers in Belgium, Croatia, Denmark, Scotland, and Sweden. Dichotomous analysis of the combined sample did not show a significant difference in expansion frequency between cases and controls. Secondary analysis after stratification for family history of affective disorder in first-degree relatives and disease severity revealed a borderline significant difference (P = 0.03) with a relative risk of 2.43 of developing bipolar disorder in familial cases homozygous for the expanded allele. This finding rendered further support to the hypothesis that SEF2-1B cannot be excluded as a susceptibility gene for bipolar disorder or that SEF2-1B is in linkage disequilibrium with a causal gene for bipolar disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12032737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Pitt-Hopkins Syndrome</em></strong></p><p>
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The Pitt-Hopkins syndrome (PTHS; <a href="/entry/610954">610954</a>) is a form of severe epileptic encephalopathy with mental retardation and intermittent hyperventilation, as well as characteristic facial gestalt. <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. <strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong> Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436254">Amiel et al. (2007)</a> studied a patient with Pitt-Hopkins syndrome by means of array-comparative genomic hybridization and found a 1.8-Mb de novo microdeletion on 18q21.1; similarly, <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> did molecular karyotyping with SNP arrays to detect a 1.2-Mb deletion on 18q21.2 in a patient. <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. <strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong> Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436254">Amiel et al. (2007)</a> identified 2 de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene (<a href="#0001">602272.0001</a> and <a href="#0002">602272.0002</a>) in 3 additional subjects with Pitt-Hopkins syndrome. They stated that this was the first evidence of a human disorder related to defects in a member of the class I basic helix-loop-helix transcription factor family (also known as the E-protein family). By sequencing the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with Pitt-Hopkins syndrome, <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> detected heterozygous stop, splice, and missense mutations in 5 patients with severe mental retardation and remarkable facial resemblance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17436254+17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> reported that both null and missense mutations impaired the interaction of TCF4 with ASCL1 (<a href="/entry/100790">100790</a>) from the PHOX-RET pathway in transactivating an E box-containing reporter construct. They concluded therefore that hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G. <strong>Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.</strong> Hum. Molec. Genet. 16: 1488-1494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17478476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17478476</a>] [<a href="https://doi.org/10.1093/hmg/ddm099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17478476">Brockschmidt et al. (2007)</a> identified a de novo 0.5-Mb microdeletion of 18q21.2 encompassing the TCF4 gene in a girl with PTHS. RT-PCR analysis showed that the deletion resulted in functional TCF4 haploinsufficiency. The deletion occurred on the paternal chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17478476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kalscheuer, V. M., Feenstra, I., Van Ravenswaaij-Arts, C. M. A., Smeets, D. F. C. M., Menzel, C., Ullmann, R., Musante, L., Ropers, H.-H. <strong>Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.</strong> Am. J. Med. Genet. 146A: 2053-2059, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18627065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18627065</a>] [<a href="https://doi.org/10.1002/ajmg.a.32419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18627065">Kalscheuer et al. (2008)</a> reported a girl with a de novo heterozygous balanced translocation t(18;20)(q21.1;q11.2) that disrupted the TCF4 gene and CHD6 gene on chromosome 20. She had mild to moderate mental retardation and minor facial anomalies, including a broad, square face, hypertelorism, flat nasal bridge, prominent ears, and a short neck. She also had mild hearing loss. However, she did not have features of the classical Pitt-Hopkins phenotype, such as breathing problems, hyperventilation, or epilepsy. PCR analysis showed that the breakpoints in TCF4 and CHD6 were in intron 3 and intron 1, respectively. Fusion transcripts were produced, with CHD6 exon 1 spliced to TCF4 exon 4. The findings indicated that not all mutations in TCF4 cause the severe PTHS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18627065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others. <strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong> J. Med. Genet. 45: 738-744, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728071</a>] [<a href="https://doi.org/10.1136/jmg.2008.060129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728071">Zweier et al. (2008)</a> identified 16 different TCF4 mutations (see, e.g., <a href="#0005">602272.0005</a>-<a href="#0006">602272.0006</a>) in 16 (14%) of 117 patients with a phenotype similar to PTHS. Thirteen of the mutations were frameshift, nonsense, or splice-site mutations, consistent with haploinsufficiency as the disease-causing mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#19" class="mim-tip-reference" title="Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., Sastry, S., Spence, J. E., Bandholz, A., Surti, U., Zonana, J., Keller, K., Meschino, W., Bejjani, B. A., Torchia, B. S., Shaffer, L. G. <strong>Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.</strong> Genet. Med. 11: 797-805, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19938247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19938247</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3181bd38a9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19938247">Rosenfeld et al. (2009)</a> identified 7 new cases of Pitt-Hopkins syndrome due to deletions of TCF4 and reviewed the 59 previously reported cases in the literature. Among their newly identified patients, all had features consistent with Pitt-Hopkins syndrome, although only 3 had breathing anomalies and none had seizures. Review of the literature indicated that although all reported patients had severe psychomotor retardation, the onset of seizures and hyperventilation episodes were limited to the first decade in most patients. Hyperventilation episodes were more common than seizures and were seen in the oldest patients, and individuals with missense TCF4 mutations were more likely to develop seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19938247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. <strong>Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.</strong> Hum. Mutat. 30: 669-676, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19235238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19235238</a>] [<a href="https://doi.org/10.1002/humu.20935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19235238">De Pontual et al. (2009)</a> identified 12 different mutations in the TCF4 gene among 13 patients with Pitt-Hopkins syndrome. A clustering of mutations in the basic domain of the E-protein indicated a mutation hotspot. In vitro studies demonstrated that wildtype TCF4 only activated the reporter construct when cotransfected with ASCL1 (<a href="/entry/100790">100790</a>) and ASCL1/TCF4 mutant heterodimers had decreased transcriptional activity compared to ASCL1/TCF4 wildtype heterodimers, consistent with a loss of TCF4 function. All mutations occurred de novo, except for 1 that was inherited from a mother who had chronic depression and epilepsy from age 20 years and was somatic mosaic for the mutation. In addition to severe mental retardation and characteristic facial features, all patients had low levels of IgM, but none showed features of an immunodeficiency. <a href="#5" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. <strong>Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.</strong> Hum. Mutat. 30: 669-676, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19235238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19235238</a>] [<a href="https://doi.org/10.1002/humu.20935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19235238">De Pontual et al. (2009)</a> noted that the patients had been diagnosed over a 12-month period, suggesting that the disorder may be more common than originally thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19235238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By mapping PTHS-associated mutations to the TCF4 gene structure, <a href="#20" class="mim-tip-reference" title="Sepp, M., Pruunsild, P., Timmusk, T. <strong>Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.</strong> Hum. Molec. Genet. 21: 2873-2888, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22460224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22460224</a>] [<a href="https://doi.org/10.1093/hmg/dds112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22460224">Sepp et al. (2012)</a> found that some PTHS-associated mutations do not damage all TCF4 alternative transcripts and may permit production of TCF4 isoforms lacking the NLS and/or shorter isoforms encoded by transcripts initiated 3-prime to the mutations. Functional analyses of PTHS-associated reading frame elongations and missense mutations demonstrated that mutant TCF4 proteins are variably impaired via different mechanisms, including protein destabilization, altered dimerization, and loss of DNA-binding and transactivation ability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22460224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Fuchs Endothelial Corneal Dystrophy 3</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Mootha, V. V., Gong, X., Ku, H.-C., Xing, C. <strong>Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 33-42, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24255041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24255041</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24255041[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/10.1167/iovs.13-12611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24255041">Mootha et al. (2014)</a> found significant association between an intronic CTG repeat in the TCF4 gene (designated CTG18.1; <a href="#0007">602272.0007</a>) and Fuchs endothelial corneal dystrophy (FECD3; <a href="/entry/613267">613267</a>), with an odds ratio of 32.3 for the expanded CTG18.1 allele. Analysis of 24 FECD families carrying an expanded CTG repeat (40 or more copies) showed that the CTG18.1 expansion segregated with disease in 18 of them, although penetrance was incomplete in 3 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24255041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 identify markers for FECD, <a href="#22" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H. <strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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/10.1167/iovs.14-14958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168903">Wieben et al. (2014)</a> sequenced the TCF4 gene region in FECD patients and controls. The authors found that although no variant correlated perfectly with disease status, the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Vasanth, S., Eghrari, A. O., Gapsis, B. C., Wang, J., Haller, N. F., Stark, W. J., Katsanis, N., Riazuddin, S. A., Gottsch, J. D. <strong>Expansion of CTG18.1 trinucleotide repeat in TCF4 is a potent driver of Fuchs' corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 4531-4536, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26200491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26200491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26200491[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/10.1167/iovs.14-16122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26200491">Vasanth et al. (2015)</a> analyzed the distribution of the expanded CTG18.1 allele in a cohort of 574 late-onset FECD patients, 354 controls, and 2 multigenerational families. Over 40 CTG repeats showed a strong association with FECD (p = 1.56 x 10(-82)). The authors delineated the threshold of expansion to 103 CTG repeats above which the allele conferred causality in 17.8% Regression analyses demonstrated a significant correlation between disease severity and age in individuals who had either a monoallelic expansion or a biallelic expansion greater than 40 repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26200491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Nakano, M., Okumura, N., Nakagawa, H., Koizumi, N., Ikeda, Y., Ueno, M., Yoshii, K., Adachi, K., Aleff, R. A., Butz, M. L., Highsmith, W. E., Tashiro, K., Wieben, E. D., Kinoshita, S., Baratz, K. H. <strong>Trinucleotide repeat expansion in the TCF4 gene in Fuchs' endothelial corneal dystrophy in Japanese.</strong> Invest. Ophthal. Vis. Sci. 56: 4865-4869, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26218914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26218914</a>] [<a href="https://doi.org/10.1167/iovs.15-17082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26218914">Nakano et al. (2015)</a> identified the intronic trinucleotide expansion (TNR), defined as greater than 50 CTG repeats, in the TCF4 gene in 12 (26%) of 47 Japanese patients with FECD and in none of 96 controls. The clinical characteristics of FECD patients with the TNR expansion were not different from those without the expansion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26218914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M. <strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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/10.1167/iovs.14-16222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722209">Mootha et al. (2015)</a> identified nuclear CUG-repeat RNA foci in corneal endothelial cells from FECD patients carrying the CTG18.1 expansion; however, no RNA foci were seen in controls. Because there was no significant difference in TCF4 expression between carriers and noncarriers of the expansion, the authors concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25722209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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/10.1074/jbc.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (<a href="/entry/606516">606516</a>) in FECD corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. <a href="#8" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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/10.1074/jbc.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 (DM1; <a href="/entry/160900">160900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 FECD patient-derived primary corneal endothelial cells, <a href="#23" class="mim-tip-reference" title="Zarouchlioti, C., Sanchez-Pintado, B., Tear, N. J. H., Klein, P., Liskova, P., Dulla, K., Semo, M., Vugler, A. A., Muthusamy, K., Dudakova, L., Levis, H. J., Skalicka, P., Hysi, P., Cheetham, M. E., Tuft, S. J., Adamson, P., Hardcastle, A. J., Davidson, A. E. <strong>Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity.</strong> Am. J. Hum. Genet. 102: 528-539, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29526280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29526280</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29526280[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29526280">Zarouchlioti et al. (2018)</a> used antisense oligonucleotide (ASO) treatment specifically targeted to the CTG18.1 repeat expansion and observed reversal of changes associated with the repeat expansion, including rescue of MBNL1 nuclear localization and reduction of downstream aberrant mRNA processing. Injection of labeled ASOs into mouse vitreous showed ASO present in corneal endothelium, keratocytes, and stroma, with accumulation in both the nuclear and perinuclear regions of endothelial and stromal cells, suggesting the potential for ASO-mediated FECD therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29526280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Math1 (ATOH1; <a href="/entry/601461">601461</a>) is a proneural transcription factor essential for establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures in mice. <a href="#9" class="mim-tip-reference" title="Flora, A., Garcia, J. J., Thaller, C., Zoghbi, H. Y. <strong>The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors.</strong> Proc. Nat. Acad. Sci. 104: 15382-15387, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17878293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0707456104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17878293">Flora et al. (2007)</a> showed that Math1 interacted with Tcf4. Tcf4 -/- mice had disrupted pontine nucleus development, and this selective deficit occurred without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Deletion of the other E protein-encoding genes did not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17878293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121909120 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909120;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=rs121909120" 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=rs121909120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 unrelated patients with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. <strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong> Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436254">Amiel et al. (2007)</a> found a heterozygous 1726C-T transition in exon 18 of the TCF4 gene, resulting in an arg576-to-trp (R576W) substitution. The mutation was found neither in the parent DNA nor in a panel of 338 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 reported by <a href="#17" class="mim-tip-reference" title="Peippo, M. M., Simola, K. O. J., Valanne, L. K., Larsen, A. T., Kahkonen, M., Auranen, M. P., Ignatius, J. <strong>Pitt-Hopkins syndrome in two patients and further definition of the phenotype.</strong> Clin. Dysmorph. 15: 47-54, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16531728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16531728</a>] [<a href="https://doi.org/10.1097/01.mcd.0000184973.14775.32" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16531728">Peippo et al. (2006)</a>, <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> found the same R576W missense mutation. <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> referred to the mutation as R576/580W. The findings were consistent with haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16531728+17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro studies, <a href="#5" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. <strong>Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.</strong> Hum. Mutat. 30: 669-676, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19235238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19235238</a>] [<a href="https://doi.org/10.1002/humu.20935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19235238">de Pontual et al. (2009)</a> demonstrated that the R576W and R576Q (<a href="#0002">602272.0002</a>) mutants both had decreased transcriptional activity even when coexpressed with ASCL1 (<a href="/entry/100790">100790</a>) as heterodimers, consistent with a loss of TCF4 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19235238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. <strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong> Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436254">Amiel et al. (2007)</a> found heterozygosity for a 1727G-A transition in exon 18 of the TCF4 gene that caused an arg576-to-gln (R576Q) substitution. The same codon was involved as in 2 other patients found to have a missense mutation by <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. <strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong> Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436254">Amiel et al. (2007)</a> (see <a href="#0001">602272.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121909122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909122;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=rs121909122" 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=rs121909122" 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=RCV000007797 OR RCV000255339 OR RCV001249620" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007797, RCV000255339, RCV001249620" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007797...</a>
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<p>In a 29-year-old male with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> found a heterozygous nonsense mutation in the TCF4 gene: an 1153C-T transition in exon 15, resulting in premature termination of the protein at arg358 (R358X). The patient had severe constipation and unmotivated laughter episodes. Parents were unavailable for testing; <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> excluded the R358X mutation in 180 healthy European control individuals, suggesting that the mutation occurred de novo. The findings were consistent with haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PITT-HOPKINS SYNDROME</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">rs587784466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587784466;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=rs587784466" 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=rs587784466" 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=RCV000147725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000147725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000147725</a>
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<p>In a 29-year-old woman with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> found a receptor splice site mutation of the TCF4 gene: IVS9-1G-C. In addition to features characteristic of Pitt-Hopkins syndrome, the patient had lymphoma, which may have been related to the TCF4 mutation. Parents were unavailable for testing; <a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al. (2007)</a> excluded the IVS9-1G-C mutation in 180 healthy European control individuals, suggesting that the mutation occurred de novo. The findings were consistent with haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PITT-HOPKINS SYNDROME</strong>
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TCF4, ARG574PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909123;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=rs121909123" 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=rs121909123" 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=RCV000007799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007799</a>
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<p>In 2 patients with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#25" class="mim-tip-reference" title="Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others. <strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong> J. Med. Genet. 45: 738-744, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728071</a>] [<a href="https://doi.org/10.1136/jmg.2008.060129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728071">Zweier et al. (2008)</a> identified a heterozygous 1721G-C transversion in exon 18 of the TCF4 gene, resulting in an arg574-to-pro (R574P) substitution in the E-box recognition motif. The mutation, which was in the same region as <a href="#0001">602272.0001</a> and <a href="#0002">602272.0002</a>, was predicted to impair the interaction of TCF4 with ASCL1 (<a href="/entry/100790">100790</a>) from the PHOX-RET pathway in transactivating an E box-containing reporter construct (<a href="#24" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. <strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong> Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/515583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17436255">Zweier et al., 2007</a>). The findings were consistent with haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18728071+17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1600861681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1600861681;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=rs1600861681" 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=rs1600861681" 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=RCV000007800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007800</a>
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<p>In a patient with Pitt-Hopkins syndrome (<a href="/entry/610954">610954</a>), <a href="#25" class="mim-tip-reference" title="Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others. <strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong> J. Med. Genet. 45: 738-744, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728071</a>] [<a href="https://doi.org/10.1136/jmg.2008.060129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728071">Zweier et al. (2008)</a> identified a heterozygous 1-bp deletion (908delC) in exon 11 of the TCF4 gene, resulting in a frameshift and premature termination. The findings were consistent with haploinsufficiency as the disease mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 3</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000186552" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000186552" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000186552</a>
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<p>In a study of 120 Caucasian probands with Fuchs endothelial corneal dystrophy (see FECD3; <a href="/entry/613267">613267</a>) and 100 controls, <a href="#14" class="mim-tip-reference" title="Mootha, V. V., Gong, X., Ku, H.-C., Xing, C. <strong>Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 33-42, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24255041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24255041</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24255041[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/10.1167/iovs.13-12611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24255041">Mootha et al. (2014)</a> found significant association between an intronic CTG repeat expansion in the TCF4 gene, designated 'CTG18.1,' and FECD (p = 6.5 x 10(-25); odds ratio, 32.3). Analysis of 24 FECD families carrying an expanded CTG repeat (40 or more copies) showed that the CTG18.1 expansion segregated with disease in 18 of them, although penetrance was incomplete in 3 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24255041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H. <strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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/10.1167/iovs.14-14958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168903">Wieben et al. (2014)</a> sequenced the TCF4 gene region in FECD patients and controls, and found TGC expansion of greater than 50 repeats in 46 (68%) of 68 FECD patients and 1 (6%) of 16 controls. No variant, including TGC expansion, correlated perfectly with disease status; <a href="#22" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H. <strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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/10.1167/iovs.14-14958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168903">Wieben et al. (2014)</a> noted that even within some families, repeat expansions occurred in both affected and unaffected individuals, including individuals over age 70 with more than 80 TGC repeats who remained unaffected. However, they stated that the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M. <strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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/10.1167/iovs.14-16222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722209">Mootha et al. (2015)</a> studied corneal endothelial tissue samples from 8 FECD patients carrying the third intron CTG18.1 repeat expansion and observed abundant discrete, punctate nuclear CUG-repeat RNA foci, the hallmark of toxic RNA, in all of them; however, no RNA foci were seen in endothelium from 7 individuals without the CTG18.1 expansion, including 1 FECD patient, 1 patient with corneal edema without guttae, and 5 controls. Noting that there was no significant difference in TCF4 expression by qPCR in FECD endothelial samples with CTG18.1 expansion compared to control endothelium, <a href="#15" class="mim-tip-reference" title="Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M. <strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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/10.1167/iovs.14-16222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722209">Mootha et al. (2015)</a> concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD with CTG18.1 triplet repeat expansion, mediated by CUG-repeat RNA foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25722209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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/10.1074/jbc.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> studied corneal endothelium and fibroblasts from FECD patients and controls and determined that the CTG-CAG trinucleotide repeat expansion is transcribed into a stable sense-strand RNA, which causes the formation of CUG RNA foci in the affected tissue. There was selective abundance of poly(CUG) RNA foci in FECD corneal endothelial cells compared to fibroblasts, suggesting that TCF4 poly(CUG) transcripts predominantly accumulate in the corneal endothelium, leading to FECD pathogenesis. The authors observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (<a href="/entry/606516">606516</a>) in patient corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. <a href="#8" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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/10.1074/jbc.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Zarouchlioti, C., Sanchez-Pintado, B., Tear, N. J. H., Klein, P., Liskova, P., Dulla, K., Semo, M., Vugler, A. A., Muthusamy, K., Dudakova, L., Levis, H. J., Skalicka, P., Hysi, P., Cheetham, M. E., Tuft, S. J., Adamson, P., Hardcastle, A. J., Davidson, A. E. <strong>Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity.</strong> Am. J. Hum. Genet. 102: 528-539, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29526280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29526280</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29526280[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.02.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29526280">Zarouchlioti et al. (2018)</a> analyzed genomic DNA from 392 white British and Czech individuals with FECD and 550 controls with age-related macular degeneration (ARMD; see <a href="/entry/602272">602272</a>) and found that the presence of greater than 50 copies of the CTG18.1 repeat conferred a more than 76-fold risk for FECD. In patient-derived primary corneal endothelial cells, the authors used antisense oligonucleotide (ASO) treatment specifically targeted to the CTG18.1 repeat expansion and observed reversal of changes associated with the repeat expansion, including rescue of MBNL1 nuclear localization and reduction of downstream aberrant mRNA processing. Injection of labeled ASOs into mouse vitreous showed ASO present in corneal endothelium, keratocytes, and stroma, with accumulation in both the nuclear and perinuclear regions of endothelial and stromal cells, suggesting the potential for ASO-mediated FECD therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29526280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1093/hmg/6.11.1855" target="_blank">Full Text</a>]
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de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others.
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[<a href="https://doi.org/10.1167/iovs.14-14958" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Zarouchlioti2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zarouchlioti, C., Sanchez-Pintado, B., Tear, N. J. H., Klein, P., Liskova, P., Dulla, K., Semo, M., Vugler, A. A., Muthusamy, K., Dudakova, L., Levis, H. J., Skalicka, P., Hysi, P., Cheetham, M. E., Tuft, S. J., Adamson, P., Hardcastle, A. J., Davidson, A. E.
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<strong>Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity.</strong>
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Am. J. Hum. Genet. 102: 528-539, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29526280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29526280</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29526280[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29526280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.02.010" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Zweier2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A.
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<strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong>
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Am. J. Hum. Genet. 80: 994-1001, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/515583" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Zweier2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others.
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<strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong>
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J. Med. Genet. 45: 738-744, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.060129" target="_blank">Full Text</a>]
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</ol>
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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="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Marla J. F. O'Neill - updated : 12/21/2018
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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 : 09/28/2016<br>Jane Kelly - updated : 04/19/2016<br>Marla J. F. O'Neill - updated : 7/21/2015<br>Matthew B. Gross - updated : 3/26/2015<br>Patricia A. Hartz - updated : 3/24/2015<br>Patricia A. Hartz - updated : 3/14/2013<br>Cassandra L. Kniffin - updated : 1/20/2011<br>Marla J. F. O'Neill - updated : 10/22/2010<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Ada Hamosh - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 12/16/2008<br>Cassandra L. Kniffin - updated : 10/20/2008<br>Patricia A. Hartz - updated : 11/15/2007<br>Patricia A. Hartz - updated : 11/9/2007<br>Ada Hamosh - updated : 6/29/2007<br>Victor A. McKusick - updated : 4/19/2007<br>Michael B. Petersen - updated : 11/7/2002<br>Victor A. McKusick - updated : 11/11/1998<br>Rebekah S. Rasooly - updated : 2/9/1998
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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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Jennifer P. Macke : 1/23/1998
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</span>
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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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<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 : 02/17/2025
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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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mgross : 12/18/2024<br>alopez : 10/31/2019<br>alopez : 12/21/2018<br>alopez : 09/28/2016<br>carol : 08/25/2016<br>carol : 04/19/2016<br>carol : 7/27/2015<br>carol : 7/24/2015<br>mcolton : 7/21/2015<br>mgross : 3/26/2015<br>mcolton : 3/24/2015<br>carol : 9/16/2013<br>mgross : 3/14/2013<br>terry : 3/14/2013<br>wwang : 2/4/2011<br>ckniffin : 1/20/2011<br>wwang : 10/26/2010<br>terry : 10/22/2010<br>wwang : 3/25/2010<br>ckniffin : 3/9/2010<br>alopez : 1/7/2010<br>terry : 1/4/2010<br>carol : 12/30/2008<br>ckniffin : 12/16/2008<br>wwang : 10/21/2008<br>ckniffin : 10/20/2008<br>mgross : 11/15/2007<br>mgross : 11/14/2007<br>terry : 11/9/2007<br>alopez : 7/2/2007<br>terry : 6/29/2007<br>alopez : 4/23/2007<br>alopez : 4/23/2007<br>terry : 4/19/2007<br>cwells : 11/7/2002<br>alopez : 3/22/1999<br>carol : 11/11/1998<br>alopez : 5/11/1998<br>alopez : 2/9/1998<br>alopez : 2/9/1998<br>alopez : 1/26/1998<br>alopez : 1/23/1998
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</span>
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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> 602272
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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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TRANSCRIPTION FACTOR 4; TCF4
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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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<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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IMMUNOGLOBULIN TRANSCRIPTION FACTOR 2; ITF2<br />
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SEF2-1B<br />
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SEF2<br />
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E2-2
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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: TCF4</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> 702344008;
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</span>
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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: 18q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:55,222,185-55,635,957 </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="2">
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<span class="mim-font">
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18q21.2
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</td>
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<td>
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<span class="mim-font">
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Corneal dystrophy, Fuchs endothelial, 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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613267
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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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</td>
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<tr>
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<td>
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<span class="mim-font">
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Pitt-Hopkins syndrome
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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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610954
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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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</td>
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</tbody>
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</table>
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<div>
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<br />
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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>TCF4 is a broadly expressed basic helix-loop-helix (bHLH) protein that functions as a homodimer or as a heterodimer with other bHLH proteins. These dimers bind DNA at Ephrussi (E) box sequences. Alternative splicing produces numerous N-terminally distinct TCF4 isoforms that differ in their subcellular localization and transactivational capacity (summary by Sepp et al., 2012). </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>Corneliussen et al. (1991) identified a family of nuclear proteins that bind to a motif of the glucocorticoid response element (GRE) in the enhancer of the murine leukemia virus SL3-3. This motif resembled those found in E boxes. Corneliussen et al. (1991) termed this family SEF2 for 'SL3-3 enhancer factors 2.' They cloned the gene encoding one of these proteins, SEF2-1B, from human thymocytes. Corneliussen et al. (1991) found that the SEF2-1B gene encodes a 667-amino acid polypeptide with homology to other bHLH transcription factors. Corneliussen et al. (1991) found multiple related mRNA species, presumed to be the result of differential splicing. </p><p>Henthorn et al. (1990) identified a helix-loop-helix transcription factor that bound to the mu-E5 motif of the immunoglobulin heavy chain enhancer and to the kappa-E2 motif found in the light chain enhancer, and designated it ITF2 for 'immunoglobulin transcription factor 2.' ITF2 encodes a predicted 623-amino acid protein (Henthorn et al., 1990). </p><p>Pscherer et al. (1996) isolated the promoter region of human somatostatin receptor-2 (SSTR2; 182452) and identified a novel initiator element. By screening a mouse brain cDNA expression library, Pscherer et al. (1996) isolated a transcription factor, which they termed Sef2, that bound to the E box of the SSTR2 initiator element. Sequencing revealed that this factor was the murine homolog of human SEF2-1B. DNA binding studies demonstrated that the basal transcription factor TFIIB (189963) can be tethered to the SSTR2 initiator element through physical interaction with SEF2. Northern blot analysis revealed that SEF2-1B is expressed in human adult and embryonic tissues including heart, brain, placenta, skeletal muscle, and lung. </p><p>In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, Breschel et al. (1997) screened a genomic human chromosome 18-specific library and identified a 1.6-kb clone with a CTG(24) repeat that mapped to 18q21.1, which they designated CTG18.1 (see 602272.0007). The expansion was located in an intron of SEF2-1. The repeat was highly polymorphic in both bipolar and control subjects with an observed heterozygosity of 84%. Expansions of up to CTG(2100) were possible but were not associated with an obvious abnormal phenotype. The location of the repeat was determined by radiation hybrid mapping and by linkage analysis. </p><p>By database analysis, Brockschmidt et al. (2007) identified the TCF4 ortholog in zebrafish. Whole-mount in situ hybridization showed expression of Tcf4 in the developing zebrafish brain. Tcf4 was first expressed in the telencephalic/diencephalic border, with later expression in the dorsal telencephalon and the diencephalon, including the thalamus, ventral thalamus and posterior tuberculum, and in the midbrain tegmentum. Tcf4 was not expressed in the hypothalamus, whereas it showed later expression in the retina and branchial arches. </p><p>De Pontual et al. (2009) found that TCF4 was highly expressed in the developing human central nervous system, sclerotomal components of the somites, the condensing vertebral body, the limb bud, splanchnopleural mesenchyme, and the gonadal ridge. It was later expressed in various nervous system tissues, thyroid, thymus, kidney, and gonads. In postnatal life, expression was observed in adult lymphocytes, fibroblasts, gut, muscle, and myenteric plexus. Expression was not seen in cardiac muscle. </p><p>Sepp et al. (2012) reported that the full-length 671-amino acid TCF4 isoform has an N-terminal transcriptional activation domain (AD1), followed by a nuclear localization signal (NLS), a second transcriptional activation domain (AD2), and a C-terminal bHLH domain that mediates dimerization and E-box binding. Alternative splicing at the 5-prime end results in TCF4 proteins with 18 different N termini. These isoforms may lack AD1 and/or NLS, but all have AD2 and bHLH domains. In addition, some isoforms lack 4 amino acids between the AD2 and bHLH domains. </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">
|
|
<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>Breschel et al. (1997) showed that the mouse Sef2-1 gene contains 22 exons, with many of the introns more than 10 kb long. </p><p>Zweier et al. (2007) determined that the human TCF4 gene contains 20 exons (exons 1 and 20 are noncoding), spans 360 kb, and encodes at least 2 isoforms that differ in the presence or absence of 4 amino acids. </p><p>Sepp et al. (2012) reported that the 5-prime end of the TCF4 gene is subject to complex alternative splicing. Exons 10 through 21 are common to all TCF4 transcripts. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Breschel et al. (1997) mapped a CTG repeat within an intron of the TCF4 gene to chromosome 18q21.1 by genomic sequence analysis. </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>DNA binding studies by Pscherer et al. (1996) demonstrated that the basal transcription factor TFIIB (189963) could be tethered to the SSTR2 initiator element through physical interaction with SEF2. </p><p>Dorflinger et al. (1999) showed that Mibp1 (HIVEP2; 143054) interacted with Sef2 to enhance transcription from the basal Sstr2 promoter in murine brain. </p><p>Luo et al. (2016) provided data indicating that PGC1-alpha (604517) suppresses melanoma (155600) metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1-alpha expression inversely correlated with vertical growth in human melanoma specimens. Mechanistically, PGC1-alpha directly increases transcription of ID2 (600386), which in turn binds to and inactivates the transcription factor TCF4. Inactive TCF4 caused downregulation of metastasis-related genes, including integrins that influence invasion and metastasis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Bipolar Affective Disorder</em></strong></p><p>
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Del-Favero et al. (2002) studied the CTG repeat in the third intron of the SEF2-1B gene in a large combined European case-control sample of bipolar affective disorder (125480). The sample consisted of 403 patients and 486 controls matched for age, gender, and ethnicity. The patients were consecutively recruited from 5 participating centers in Belgium, Croatia, Denmark, Scotland, and Sweden. Dichotomous analysis of the combined sample did not show a significant difference in expansion frequency between cases and controls. Secondary analysis after stratification for family history of affective disorder in first-degree relatives and disease severity revealed a borderline significant difference (P = 0.03) with a relative risk of 2.43 of developing bipolar disorder in familial cases homozygous for the expanded allele. This finding rendered further support to the hypothesis that SEF2-1B cannot be excluded as a susceptibility gene for bipolar disorder or that SEF2-1B is in linkage disequilibrium with a causal gene for bipolar disorder. </p><p><strong><em>Pitt-Hopkins Syndrome</em></strong></p><p>
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The Pitt-Hopkins syndrome (PTHS; 610954) is a form of severe epileptic encephalopathy with mental retardation and intermittent hyperventilation, as well as characteristic facial gestalt. Amiel et al. (2007) studied a patient with Pitt-Hopkins syndrome by means of array-comparative genomic hybridization and found a 1.8-Mb de novo microdeletion on 18q21.1; similarly, Zweier et al. (2007) did molecular karyotyping with SNP arrays to detect a 1.2-Mb deletion on 18q21.2 in a patient. Amiel et al. (2007) identified 2 de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene (602272.0001 and 602272.0002) in 3 additional subjects with Pitt-Hopkins syndrome. They stated that this was the first evidence of a human disorder related to defects in a member of the class I basic helix-loop-helix transcription factor family (also known as the E-protein family). By sequencing the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with Pitt-Hopkins syndrome, Zweier et al. (2007) detected heterozygous stop, splice, and missense mutations in 5 patients with severe mental retardation and remarkable facial resemblance. </p><p>Zweier et al. (2007) reported that both null and missense mutations impaired the interaction of TCF4 with ASCL1 (100790) from the PHOX-RET pathway in transactivating an E box-containing reporter construct. They concluded therefore that hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives. </p><p>Brockschmidt et al. (2007) identified a de novo 0.5-Mb microdeletion of 18q21.2 encompassing the TCF4 gene in a girl with PTHS. RT-PCR analysis showed that the deletion resulted in functional TCF4 haploinsufficiency. The deletion occurred on the paternal chromosome. </p><p>Kalscheuer et al. (2008) reported a girl with a de novo heterozygous balanced translocation t(18;20)(q21.1;q11.2) that disrupted the TCF4 gene and CHD6 gene on chromosome 20. She had mild to moderate mental retardation and minor facial anomalies, including a broad, square face, hypertelorism, flat nasal bridge, prominent ears, and a short neck. She also had mild hearing loss. However, she did not have features of the classical Pitt-Hopkins phenotype, such as breathing problems, hyperventilation, or epilepsy. PCR analysis showed that the breakpoints in TCF4 and CHD6 were in intron 3 and intron 1, respectively. Fusion transcripts were produced, with CHD6 exon 1 spliced to TCF4 exon 4. The findings indicated that not all mutations in TCF4 cause the severe PTHS phenotype. </p><p>Zweier et al. (2008) identified 16 different TCF4 mutations (see, e.g., 602272.0005-602272.0006) in 16 (14%) of 117 patients with a phenotype similar to PTHS. Thirteen of the mutations were frameshift, nonsense, or splice-site mutations, consistent with haploinsufficiency as the disease-causing mechanism. </p><p>Rosenfeld et al. (2009) identified 7 new cases of Pitt-Hopkins syndrome due to deletions of TCF4 and reviewed the 59 previously reported cases in the literature. Among their newly identified patients, all had features consistent with Pitt-Hopkins syndrome, although only 3 had breathing anomalies and none had seizures. Review of the literature indicated that although all reported patients had severe psychomotor retardation, the onset of seizures and hyperventilation episodes were limited to the first decade in most patients. Hyperventilation episodes were more common than seizures and were seen in the oldest patients, and individuals with missense TCF4 mutations were more likely to develop seizures. </p><p>De Pontual et al. (2009) identified 12 different mutations in the TCF4 gene among 13 patients with Pitt-Hopkins syndrome. A clustering of mutations in the basic domain of the E-protein indicated a mutation hotspot. In vitro studies demonstrated that wildtype TCF4 only activated the reporter construct when cotransfected with ASCL1 (100790) and ASCL1/TCF4 mutant heterodimers had decreased transcriptional activity compared to ASCL1/TCF4 wildtype heterodimers, consistent with a loss of TCF4 function. All mutations occurred de novo, except for 1 that was inherited from a mother who had chronic depression and epilepsy from age 20 years and was somatic mosaic for the mutation. In addition to severe mental retardation and characteristic facial features, all patients had low levels of IgM, but none showed features of an immunodeficiency. De Pontual et al. (2009) noted that the patients had been diagnosed over a 12-month period, suggesting that the disorder may be more common than originally thought. </p><p>By mapping PTHS-associated mutations to the TCF4 gene structure, Sepp et al. (2012) found that some PTHS-associated mutations do not damage all TCF4 alternative transcripts and may permit production of TCF4 isoforms lacking the NLS and/or shorter isoforms encoded by transcripts initiated 3-prime to the mutations. Functional analyses of PTHS-associated reading frame elongations and missense mutations demonstrated that mutant TCF4 proteins are variably impaired via different mechanisms, including protein destabilization, altered dimerization, and loss of DNA-binding and transactivation ability. </p><p><strong><em>Fuchs Endothelial Corneal Dystrophy 3</em></strong></p><p>
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|
Mootha et al. (2014) found significant association between an intronic CTG repeat in the TCF4 gene (designated CTG18.1; 602272.0007) and Fuchs endothelial corneal dystrophy (FECD3; 613267), with an odds ratio of 32.3 for the expanded CTG18.1 allele. Analysis of 24 FECD families carrying an expanded CTG repeat (40 or more copies) showed that the CTG18.1 expansion segregated with disease in 18 of them, although penetrance was incomplete in 3 families. </p><p>To identify markers for FECD, Wieben et al. (2014) sequenced the TCF4 gene region in FECD patients and controls. The authors found that although no variant correlated perfectly with disease status, the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. </p><p>Vasanth et al. (2015) analyzed the distribution of the expanded CTG18.1 allele in a cohort of 574 late-onset FECD patients, 354 controls, and 2 multigenerational families. Over 40 CTG repeats showed a strong association with FECD (p = 1.56 x 10(-82)). The authors delineated the threshold of expansion to 103 CTG repeats above which the allele conferred causality in 17.8% Regression analyses demonstrated a significant correlation between disease severity and age in individuals who had either a monoallelic expansion or a biallelic expansion greater than 40 repeats. </p><p>Nakano et al. (2015) identified the intronic trinucleotide expansion (TNR), defined as greater than 50 CTG repeats, in the TCF4 gene in 12 (26%) of 47 Japanese patients with FECD and in none of 96 controls. The clinical characteristics of FECD patients with the TNR expansion were not different from those without the expansion. </p><p>Mootha et al. (2015) identified nuclear CUG-repeat RNA foci in corneal endothelial cells from FECD patients carrying the CTG18.1 expansion; however, no RNA foci were seen in controls. Because there was no significant difference in TCF4 expression between carriers and noncarriers of the expansion, the authors concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD. </p><p>Du et al. (2015) observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (606516) in FECD corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. Du et al. (2015) concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 (DM1; 160900). </p><p>In FECD patient-derived primary corneal endothelial cells, Zarouchlioti et al. (2018) used antisense oligonucleotide (ASO) treatment specifically targeted to the CTG18.1 repeat expansion and observed reversal of changes associated with the repeat expansion, including rescue of MBNL1 nuclear localization and reduction of downstream aberrant mRNA processing. Injection of labeled ASOs into mouse vitreous showed ASO present in corneal endothelium, keratocytes, and stroma, with accumulation in both the nuclear and perinuclear regions of endothelial and stromal cells, suggesting the potential for ASO-mediated FECD therapy. </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>Math1 (ATOH1; 601461) is a proneural transcription factor essential for establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures in mice. Flora et al. (2007) showed that Math1 interacted with Tcf4. Tcf4 -/- mice had disrupted pontine nucleus development, and this selective deficit occurred without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Deletion of the other E protein-encoding genes did not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 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 PITT-HOPKINS SYNDROME</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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TCF4, ARG576TRP
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<br />
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SNP: rs121909120,
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ClinVar: RCV000007795, RCV000387138, RCV000415008, RCV001266245
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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 2 unrelated patients with Pitt-Hopkins syndrome (610954), Amiel et al. (2007) found a heterozygous 1726C-T transition in exon 18 of the TCF4 gene, resulting in an arg576-to-trp (R576W) substitution. The mutation was found neither in the parent DNA nor in a panel of 338 control chromosomes. </p><p>In a patient reported by Peippo et al. (2006), Zweier et al. (2007) found the same R576W missense mutation. Zweier et al. (2007) referred to the mutation as R576/580W. The findings were consistent with haploinsufficiency as the disease mechanism. </p><p>By in vitro studies, de Pontual et al. (2009) demonstrated that the R576W and R576Q (602272.0002) mutants both had decreased transcriptional activity even when coexpressed with ASCL1 (100790) as heterodimers, consistent with a loss of TCF4 function. </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 PITT-HOPKINS SYNDROME</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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TCF4, ARG576GLN
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<br />
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SNP: rs121909121,
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gnomAD: rs121909121,
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ClinVar: RCV000007796, RCV000189725
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with Pitt-Hopkins syndrome (610954), Amiel et al. (2007) found heterozygosity for a 1727G-A transition in exon 18 of the TCF4 gene that caused an arg576-to-gln (R576Q) substitution. The same codon was involved as in 2 other patients found to have a missense mutation by Amiel et al. (2007) (see 602272.0001). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 PITT-HOPKINS SYNDROME</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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TCF4, ARG358TER
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<br />
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SNP: rs121909122,
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ClinVar: RCV000007797, RCV000255339, RCV001249620
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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 29-year-old male with Pitt-Hopkins syndrome (610954), Zweier et al. (2007) found a heterozygous nonsense mutation in the TCF4 gene: an 1153C-T transition in exon 15, resulting in premature termination of the protein at arg358 (R358X). The patient had severe constipation and unmotivated laughter episodes. Parents were unavailable for testing; Zweier et al. (2007) excluded the R358X mutation in 180 healthy European control individuals, suggesting that the mutation occurred de novo. The findings were consistent with haploinsufficiency as the disease mechanism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 PITT-HOPKINS SYNDROME</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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TCF4, IVS9AS, G-C, -1
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<br />
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SNP: rs587784466,
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ClinVar: RCV000147725
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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 29-year-old woman with Pitt-Hopkins syndrome (610954), Zweier et al. (2007) found a receptor splice site mutation of the TCF4 gene: IVS9-1G-C. In addition to features characteristic of Pitt-Hopkins syndrome, the patient had lymphoma, which may have been related to the TCF4 mutation. Parents were unavailable for testing; Zweier et al. (2007) excluded the IVS9-1G-C mutation in 180 healthy European control individuals, suggesting that the mutation occurred de novo. The findings were consistent with haploinsufficiency as the disease mechanism. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 PITT-HOPKINS SYNDROME</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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TCF4, ARG574PRO
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<br />
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|
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SNP: rs121909123,
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ClinVar: RCV000007799
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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 2 patients with Pitt-Hopkins syndrome (610954), Zweier et al. (2008) identified a heterozygous 1721G-C transversion in exon 18 of the TCF4 gene, resulting in an arg574-to-pro (R574P) substitution in the E-box recognition motif. The mutation, which was in the same region as 602272.0001 and 602272.0002, was predicted to impair the interaction of TCF4 with ASCL1 (100790) from the PHOX-RET pathway in transactivating an E box-containing reporter construct (Zweier et al., 2007). The findings were consistent with haploinsufficiency as the disease mechanism. </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>
|
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<span class="mim-font">
|
|
<strong>.0006 PITT-HOPKINS SYNDROME</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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TCF4, 1-BP DEL, 908C
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<br />
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SNP: rs1600861681,
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ClinVar: RCV000007800
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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 patient with Pitt-Hopkins syndrome (610954), Zweier et al. (2008) identified a heterozygous 1-bp deletion (908delC) in exon 11 of the TCF4 gene, resulting in a frameshift and premature termination. The findings were consistent with haploinsufficiency as the disease mechanism. </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>
|
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<span class="mim-font">
|
|
<strong>.0007 CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 3</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TCF4, (CTG)n REPEAT EXPANSION, IVS3
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<br />
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ClinVar: RCV000186552
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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 study of 120 Caucasian probands with Fuchs endothelial corneal dystrophy (see FECD3; 613267) and 100 controls, Mootha et al. (2014) found significant association between an intronic CTG repeat expansion in the TCF4 gene, designated 'CTG18.1,' and FECD (p = 6.5 x 10(-25); odds ratio, 32.3). Analysis of 24 FECD families carrying an expanded CTG repeat (40 or more copies) showed that the CTG18.1 expansion segregated with disease in 18 of them, although penetrance was incomplete in 3 families. </p><p>Wieben et al. (2014) sequenced the TCF4 gene region in FECD patients and controls, and found TGC expansion of greater than 50 repeats in 46 (68%) of 68 FECD patients and 1 (6%) of 16 controls. No variant, including TGC expansion, correlated perfectly with disease status; Wieben et al. (2014) noted that even within some families, repeat expansions occurred in both affected and unaffected individuals, including individuals over age 70 with more than 80 TGC repeats who remained unaffected. However, they stated that the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. </p><p>Mootha et al. (2015) studied corneal endothelial tissue samples from 8 FECD patients carrying the third intron CTG18.1 repeat expansion and observed abundant discrete, punctate nuclear CUG-repeat RNA foci, the hallmark of toxic RNA, in all of them; however, no RNA foci were seen in endothelium from 7 individuals without the CTG18.1 expansion, including 1 FECD patient, 1 patient with corneal edema without guttae, and 5 controls. Noting that there was no significant difference in TCF4 expression by qPCR in FECD endothelial samples with CTG18.1 expansion compared to control endothelium, Mootha et al. (2015) concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD with CTG18.1 triplet repeat expansion, mediated by CUG-repeat RNA foci. </p><p>Du et al. (2015) studied corneal endothelium and fibroblasts from FECD patients and controls and determined that the CTG-CAG trinucleotide repeat expansion is transcribed into a stable sense-strand RNA, which causes the formation of CUG RNA foci in the affected tissue. There was selective abundance of poly(CUG) RNA foci in FECD corneal endothelial cells compared to fibroblasts, suggesting that TCF4 poly(CUG) transcripts predominantly accumulate in the corneal endothelium, leading to FECD pathogenesis. The authors observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (606516) in patient corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. Du et al. (2015) concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci. </p><p>Zarouchlioti et al. (2018) analyzed genomic DNA from 392 white British and Czech individuals with FECD and 550 controls with age-related macular degeneration (ARMD; see 602272) and found that the presence of greater than 50 copies of the CTG18.1 repeat conferred a more than 76-fold risk for FECD. In patient-derived primary corneal endothelial cells, the authors used antisense oligonucleotide (ASO) treatment specifically targeted to the CTG18.1 repeat expansion and observed reversal of changes associated with the repeat expansion, including rescue of MBNL1 nuclear localization and reduction of downstream aberrant mRNA processing. Injection of labeled ASOs into mouse vitreous showed ASO present in corneal endothelium, keratocytes, and stroma, with accumulation in both the nuclear and perinuclear regions of endothelial and stromal cells, suggesting the potential for ASO-mediated FECD therapy. </p>
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Marla J. F. O'Neill - updated : 12/21/2018<br>Ada Hamosh - updated : 09/28/2016<br>Jane Kelly - updated : 04/19/2016<br>Marla J. F. O'Neill - updated : 7/21/2015<br>Matthew B. Gross - updated : 3/26/2015<br>Patricia A. Hartz - updated : 3/24/2015<br>Patricia A. Hartz - updated : 3/14/2013<br>Cassandra L. Kniffin - updated : 1/20/2011<br>Marla J. F. O'Neill - updated : 10/22/2010<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Ada Hamosh - updated : 1/4/2010<br>Cassandra L. Kniffin - updated : 12/16/2008<br>Cassandra L. Kniffin - updated : 10/20/2008<br>Patricia A. Hartz - updated : 11/15/2007<br>Patricia A. Hartz - updated : 11/9/2007<br>Ada Hamosh - updated : 6/29/2007<br>Victor A. McKusick - updated : 4/19/2007<br>Michael B. Petersen - updated : 11/7/2002<br>Victor A. McKusick - updated : 11/11/1998<br>Rebekah S. Rasooly - updated : 2/9/1998
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Jennifer P. Macke : 1/23/1998
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carol : 02/17/2025<br>mgross : 12/18/2024<br>alopez : 10/31/2019<br>alopez : 12/21/2018<br>alopez : 09/28/2016<br>carol : 08/25/2016<br>carol : 04/19/2016<br>carol : 7/27/2015<br>carol : 7/24/2015<br>mcolton : 7/21/2015<br>mgross : 3/26/2015<br>mcolton : 3/24/2015<br>carol : 9/16/2013<br>mgross : 3/14/2013<br>terry : 3/14/2013<br>wwang : 2/4/2011<br>ckniffin : 1/20/2011<br>wwang : 10/26/2010<br>terry : 10/22/2010<br>wwang : 3/25/2010<br>ckniffin : 3/9/2010<br>alopez : 1/7/2010<br>terry : 1/4/2010<br>carol : 12/30/2008<br>ckniffin : 12/16/2008<br>wwang : 10/21/2008<br>ckniffin : 10/20/2008<br>mgross : 11/15/2007<br>mgross : 11/14/2007<br>terry : 11/9/2007<br>alopez : 7/2/2007<br>terry : 6/29/2007<br>alopez : 4/23/2007<br>alopez : 4/23/2007<br>terry : 4/19/2007<br>cwells : 11/7/2002<br>alopez : 3/22/1999<br>carol : 11/11/1998<br>alopez : 5/11/1998<br>alopez : 2/9/1998<br>alopez : 2/9/1998<br>alopez : 1/26/1998<br>alopez : 1/23/1998
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