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Entry
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- *603273 - TUMOR PROTEIN p63; TP63
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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">*603273</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/603273">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000073282;t=ENST00000264731" 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=8626" 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=603273" 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=ENSG00000073282;t=ENST00000264731" 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_001114978,NM_001114979,NM_001114980,NM_001114981,NM_001114982,NM_001329144,NM_001329145,NM_001329146,NM_001329148,NM_001329149,NM_001329150,NM_001329964,NM_003722" 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_003722" 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=603273" 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=04469&isoform_id=04469_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/TP63" 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/3445484,3510328,3510330,3644040,3695078,3695080,3695082,3695084,3695086,3695088,3970717,7248445,7248446,7248447,7248448,7248449,7248450,7248451,7248452,7384976,12024744,12024745,12024746,12024747,12024748,12024749,12060406,15072750,24980977,31543818,34304695,57013009,119598518,119598519,119598520,119598521,119598522,119598523,119598524,119598525,119598526,169234657,169234659,169234661,169234663,169234665,221044870,257449248,257449250,549269910,957950506,957950509,984944558,984944573,984944587,1041817926,1041817938,1041817940,1041817948,1041817975,1041818010,1051791003" 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/Q9H3D4" 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=8626" 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=ENSG00000073282;t=ENST00000264731" 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=TP63" 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=TP63" 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+8626" 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/TP63" 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:8626" 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/8626" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000820570.1&hgg_start=189596746&hgg_end=189897276&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:15979" 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:15979" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603273[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=603273[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/TP63/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/ENSG00000073282" 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=TP63" 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=TP63" 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=TP63" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://grenada.lumc.nl/LOVD2/ARVC/home.php?select_db=TP63" title="ARVD/C Genetic Variants Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ARVD/C Genetic Variants Da…</a></div><div style="margin-left: 0.5em;"><a href="http://www.arvcdatabase.info" title="ARVD/C Genes Variants Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ARVD/C Genes Variants Data…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=TP63&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/PA162406776" 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:15979" 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/FBgn0039044.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:1330810" 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/TP63#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:1330810" 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/8626/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=8626" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030819-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:8626" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=TP63&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> 55821006, 720464003, 721972001, 7731005<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>
|
|
603273
|
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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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TUMOR PROTEIN p63; TP63
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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>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
TUMOR PROTEIN p73-LIKE; TP73L<br />
|
|
p53-RELATED PROTEIN p63; p63<br />
|
|
KET
|
|
</span>
|
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</h4>
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TP63" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TP63</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/957?start=-3&limit=10&highlight=957">3q28</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:189596746-189897276&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:189,596,746-189,897,276</a> </span>
|
|
</em>
|
|
</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>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=103285,604292,106260,603543,618149,620311,129400,605289" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="8">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/957?start=-3&limit=10&highlight=957">
|
|
3q28
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
ADULT 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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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/radial/603273" 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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<p><a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a> described the cloning of tumor protein p63, which shows strong homology to the tumor suppressor p53 (<a href="/entry/191170">191170</a>) and the p53-related protein p73 (<a href="/entry/601990">601990</a>). p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. The p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. The predominant p63 isoforms in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. The full-length p63 protein contains 448 amino acids. Isoforms of p63 are due to alternative promoters in exons 1 or 3 and alternative splicing of exons at the 3-prime end. These truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63. <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a> suggested the possibility of physiologic interactions among members of the p53 family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774969" 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="Augustin, M., Bamberger, C., Paul, D., Schmale, H. <strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong> Mammalian Genome 9: 899-902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799841</a>] [<a href="https://doi.org/10.1007/s003359900891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9799841">Augustin et al. (1998)</a> also cloned a cDNA, which they termed KET, that is related to the tumor suppressor p53. They stated that the 4,846-bp KET cDNA encodes a protein of 680 amino acids that shares 98% identity with the rat homolog. The remarkable degree of conservation lent support to the notion that KET proteins have important basic functions in development and differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9799841" 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="Di Iorio, E., Barbaro, V., Ruzza, A., Ponzin, D., Pellegrini, G., De Luca, M. <strong>Isoforms of delta-N-p63 and the migration of ocular limbal cells in human corneal regeneration.</strong> Proc. Nat. Acad. Sci. 102: 9523-9528, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15983386[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.0503437102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983386">Di Iorio et al. (2005)</a> stated that the p63 gene generates 6 isoforms. The transactivating isoforms are generated by the activity of an upstream promoter, and the N-terminally truncated (delta-N) isoforms, which lack the transactivation domain, are produced from a downstream intronic promoter. For both transcripts, alternative splicing gives rise to 3 different C termini, designated alpha, beta, and gamma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15983386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Deutsch, G. B., Zielonka, E. M., Coutandin, D., Weber, T. A., Schafer, B., Hannewald, J., Luh, L. M., Durst, F. G., Ibrahim, M., Hoffmann, J., Niesen, F. H., Senturk, A., Kunkel, H., Brutschy, B., Schleiff, E., Knapp, S., Acker-Palmer, A., Grez, M., McKeon, F., Dotsch, V. <strong>DNA damage in oocytes induces a switch of the quality control factor TAp63-alpha from dimer to tetramer.</strong> Cell 144: 566-576, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21335238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21335238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21335238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2011.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21335238">Deutsch et al. (2011)</a> stated that full-length TAp63-alpha contains an N-terminal transactivation domain, followed by a DNA-binding domain, an oligomerization domain, a sterile-alpha motif (SAM) domain, and a C-terminal transactivation inhibitory (TI) domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21335238" 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="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a> determined that the TP63 gene contains 15 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By fluorescence in situ hybridization, <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a> localized the human TP63 gene to chromosome 3q27-q29. Using linkage analysis, they mapped the mouse gene to chromosome 16 in a region known to be syntenic with human 3q27-q29. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774969" 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 radiation hybrid analysis, <a href="#3" class="mim-tip-reference" title="Augustin, M., Bamberger, C., Paul, D., Schmale, H. <strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong> Mammalian Genome 9: 899-902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799841</a>] [<a href="https://doi.org/10.1007/s003359900891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9799841">Augustin et al. (1998)</a> mapped the TP63 gene to human chromosome 3q27. KET (TP63) is located between the somatostatin gene (SST; <a href="/entry/182450">182450</a>) proximally and the apolipoprotein D gene (APOD; <a href="/entry/107740">107740</a>) distally. By means of an interspecific backcross panel, <a href="#3" class="mim-tip-reference" title="Augustin, M., Bamberger, C., Paul, D., Schmale, H. <strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong> Mammalian Genome 9: 899-902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799841</a>] [<a href="https://doi.org/10.1007/s003359900891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9799841">Augustin et al. (1998)</a> mapped the murine homolog, Ket, to chromosome 16 in a region that is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the Loh2 gene, a putative suppressor of angiogenesis. <a href="#3" class="mim-tip-reference" title="Augustin, M., Bamberger, C., Paul, D., Schmale, H. <strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong> Mammalian Genome 9: 899-902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799841</a>] [<a href="https://doi.org/10.1007/s003359900891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9799841">Augustin et al. (1998)</a> inferred from mapping data that KET may act as a tumor suppressor and should be considered a candidate for Loh2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9799841" 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="#21" class="mim-tip-reference" title="Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., Sidransky, D. <strong>AIS is an oncogene amplified in squamous cell carcinoma.</strong> Proc. Nat. Acad. Sci. 97: 5462-5467, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10805802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10805802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10805802[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.97.10.5462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10805802">Hibi et al. (2000)</a> stated that p53 (<a href="/entry/191170">191170</a>) homologs known variously as p40, p51, p63, and p73L (<a href="#53" class="mim-tip-reference" title="Trink, B., Okami, K., Wu, L., Sriuranpong, V., Jen, J., Sidransky, D. <strong>A new human p53 homologue. (Letter)</strong> Nature Med. 4: 747-748, 1998. Note: Erratum: Nature Med. 4: 982 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662346</a>] [<a href="https://doi.org/10.1038/nm0798-747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662346">Trink et al., 1998</a>, <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al., 1998</a>, <a href="#37" class="mim-tip-reference" title="Osada, M., Ohba, M., Kawahara, C., Ishioka, C., Kanamaru, R., Katoh, I., Ikawa, Y., Nimura, Y., Nakagawara, A., Obinata, M., Ikawa, S. <strong>Cloning and functional analysis of human p51, which structurally and functionally resembles p53.</strong> Nature Med. 4: 839-843, 1998. Note: Erratum: Nature Med. 4: 982 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662378</a>] [<a href="https://doi.org/10.1038/nm0798-839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662378">Osada et al., 1998</a>, <a href="#46" class="mim-tip-reference" title="Senoo, M., Seki, N., Ohira, M., Sugano, S., Watanabe, M., Inuzuka, S., Okamoto, T., Tachibana, M., Tanaka, T., Shinkai, Y., Kato, H. <strong>A second p53-related protein, p73L, with high homology to p73.</strong> Biochem. Biophys. Res. Commun. 248: 603-607, 1998. Note: Erratum: Biochem. Biophys. Res. Commun. 250: 536 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9703973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9703973</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9703973">Senoo et al., 1998</a>) are isoforms of the same gene, which <a href="#21" class="mim-tip-reference" title="Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., Sidransky, D. <strong>AIS is an oncogene amplified in squamous cell carcinoma.</strong> Proc. Nat. Acad. Sci. 97: 5462-5467, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10805802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10805802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10805802[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.97.10.5462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10805802">Hibi et al. (2000)</a> referred to as AIS for 'amplified in squamous cell carcinoma.' The main difference between the various transcripts is the presence or absence of the N-terminal transcriptional activation domain; p40, delta-Np63, and p73L lack this domain. Though no evidence of a tumor suppressor function was found, <a href="#21" class="mim-tip-reference" title="Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., Sidransky, D. <strong>AIS is an oncogene amplified in squamous cell carcinoma.</strong> Proc. Nat. Acad. Sci. 97: 5462-5467, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10805802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10805802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10805802[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.97.10.5462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10805802">Hibi et al. (2000)</a> observed overexpression of this gene in head and neck cancer cell lines and primary lung cancers associated with a low increase of its copy number. Amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68(AIS) lacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Results were interpreted as indicating that AIS transcripts lacking the N-terminal transcriptional activation domain play an oncogenic rather than a suppressive role in certain cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10805802+9662346+9774969+9703973+9662378" 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="Flores, E. R., Tsai, K. Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T. <strong>p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.</strong> Nature 416: 560-564, 2002. Note: Expression of Concern: Nature 627: E10, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932750</a>] [<a href="https://doi.org/10.1038/416560a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932750">Flores et al. (2002)</a> explored the role of p63 and p73 in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for 1 or a combination of these p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene. While using the E1A system facilitated the performance of biochemical analyses, the authors also examined the functions of p63 and p73 using an in vivo system in which apoptosis had been shown to be dependent on p53. Using both systems, <a href="#18" class="mim-tip-reference" title="Flores, E. R., Tsai, K. Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T. <strong>p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.</strong> Nature 416: 560-564, 2002. Note: Expression of Concern: Nature 627: E10, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932750</a>] [<a href="https://doi.org/10.1038/416560a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932750">Flores et al. (2002)</a> demonstrated that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage. Note that an Expression of Concern was published for the article by <a href="#18" class="mim-tip-reference" title="Flores, E. R., Tsai, K. Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T. <strong>p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.</strong> Nature 416: 560-564, 2002. Note: Expression of Concern: Nature 627: E10, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11932750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11932750</a>] [<a href="https://doi.org/10.1038/416560a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11932750">Flores et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11932750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Benard, J., Douc-Rasy, S., Ahomadegbe, J.-C. <strong>TP53 family members and human cancers.</strong> Hum. Mutat. 21: 182-191, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12619104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12619104</a>] [<a href="https://doi.org/10.1002/humu.10172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12619104">Benard et al. (2003)</a> suggested that the 2 homologs of TP53, TP73 and TP63, must not have a typical tumor suppressor gene role in human cancers, given the lack of demonstrated mutations in either of these 2 genes. Nevertheless, TP73 and TP63 seem strongly involved in malignancy acquisition and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12619104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using DNA microarray analysis with transfected human SAOS2 osteosarcoma cells, <a href="#62" class="mim-tip-reference" title="Wu, G., Nomoto, S., Hoque, M. O., Dracheva, T., Osada, M., Lee, C.-C. R., Dong, S. M., Guo, Z., Benoit, N., Cohen, Y., Rechthand, P., Califano, J., Moon, C., Ratovitski, E., Jen, J., Sidransky, D., Trink, B. <strong>Delta-Np63-alpha and TAp63-alpha regulate transcription of genes with distinct biological functions in cancer and development.</strong> Cancer Res. 63: 2351-2357, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750249</a>]" pmid="12750249">Wu et al. (2003)</a> found that both delta-Np63-alpha and TAp63-alpha could activate gene transcription. A comparison of gene profiles revealed that these p63 isoforms influenced a wide variety of partly overlapping targets involved in cell cycle control, stress, and signal transduction. Delta-Np63-alpha and TAp63-alpha often influenced expression of specific genes in an opposite manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750249" 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="Di Iorio, E., Barbaro, V., Ruzza, A., Ponzin, D., Pellegrini, G., De Luca, M. <strong>Isoforms of delta-N-p63 and the migration of ocular limbal cells in human corneal regeneration.</strong> Proc. Nat. Acad. Sci. 102: 9523-9528, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15983386[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.0503437102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983386">Di Iorio et al. (2005)</a> found that, depending on the conditions, limbal and corneal keratinocytes may contain all 3 delta-N isoforms of p63. In the uninjured surface of the eye, delta-N p63-alpha was present in the limbus but was absent from the corneal epithelium. Delta-N p63-beta and delta-N p63-gamma appeared upon wounding, and their expression correlated with limbal cell migration and corneal regeneration and differentiation. <a href="#15" class="mim-tip-reference" title="Di Iorio, E., Barbaro, V., Ruzza, A., Ponzin, D., Pellegrini, G., De Luca, M. <strong>Isoforms of delta-N-p63 and the migration of ocular limbal cells in human corneal regeneration.</strong> Proc. Nat. Acad. Sci. 102: 9523-9528, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15983386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15983386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15983386[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.0503437102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15983386">Di Iorio et al. (2005)</a> concluded that the alpha isoform is necessary for maintenance of the proliferative potential of limbal stem cells and their ability to migrate over the cornea. The beta and gamma isoforms, being suprabasal and virtually absent from the resting limbus, likely play a role in epithelial differentiation during corneal regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15983386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Suh, E.-K., Yang, A., Kettenbach, A., Bamberger, C., Michaelis, A. H., Zhu, Z., Elvin, J. A., Bronson, R. T., Crum, C. P., McKeon, F. <strong>p63 protects the female germ line during meiotic arrest.</strong> Nature 444: 624-628, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17122775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17122775</a>] [<a href="https://doi.org/10.1038/nature05337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17122775">Suh et al. (2006)</a> showed that p63, and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. They also showed that DNA damage induced both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. <a href="#51" class="mim-tip-reference" title="Suh, E.-K., Yang, A., Kettenbach, A., Bamberger, C., Michaelis, A. H., Zhu, Z., Elvin, J. A., Bronson, R. T., Crum, C. P., McKeon, F. <strong>p63 protects the female germ line during meiotic arrest.</strong> Nature 444: 624-628, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17122775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17122775</a>] [<a href="https://doi.org/10.1038/nature05337" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17122775">Suh et al. (2006)</a> concluded that their data supported a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germline, whereas the functions of p53 are restricted to vertebrate somatic cells for tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17122775" 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="#65" class="mim-tip-reference" title="Yi, R., Poy, M. N., Stoffel, M., Fuchs, E. <strong>A skin microRNA promotes differentiation by repressing 'stemness.'</strong> Nature 452: 225-229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18311128[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/nature06642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311128">Yi et al. (2008)</a> showed that miR203 (<a href="/entry/611899">611899</a>) is induced in the skin concomitantly with stratification and differentiation. By altering miR203's spatiotemporal expression in vivo, they showed that miR203 promotes epidermal differentiation by restricting proliferative potential and inducing cell cycle exit. <a href="#65" class="mim-tip-reference" title="Yi, R., Poy, M. N., Stoffel, M., Fuchs, E. <strong>A skin microRNA promotes differentiation by repressing 'stemness.'</strong> Nature 452: 225-229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18311128[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/nature06642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311128">Yi et al. (2008)</a> identified p63 as one of the conserved targets of miR203 across vertebrates. Notably, p63 is an essential regulator of stem cell maintenance in stratified epithelial tissues. <a href="#65" class="mim-tip-reference" title="Yi, R., Poy, M. N., Stoffel, M., Fuchs, E. <strong>A skin microRNA promotes differentiation by repressing 'stemness.'</strong> Nature 452: 225-229, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18311128[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/nature06642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18311128">Yi et al. (2008)</a> showed that miR203 directly represses the expression of p63; it fails to switch off suprabasally when either Dicer1 (<a href="/entry/606241">606241</a>) or miR203 is absent and it becomes repressed basally when miR203 is prematurely expressed. The authors concluded that miR203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighboring layers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18311128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y.-L., Leung, M. L., El-Naggar, A., Creighton, C. J., Suraokar, M. B., Wistuba, I., Flores, E. R. <strong>TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.</strong> Nature 467: 986-990, 2010. Note: Erratum: Nature 632: E2, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20962848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20962848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20962848[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/nature09459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20962848">Su et al. (2010)</a> showed that TAp63 suppresses tumorigenesis and metastasis, and coordinately regulates Dicer (<a href="/entry/606241">606241</a>) and miR130b (<a href="/entry/613682">613682</a>) to suppress metastasis. Metastatic mouse and human tumors deficient in TAp63 express Dicer at very low levels, and <a href="#50" class="mim-tip-reference" title="Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y.-L., Leung, M. L., El-Naggar, A., Creighton, C. J., Suraokar, M. B., Wistuba, I., Flores, E. R. <strong>TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.</strong> Nature 467: 986-990, 2010. Note: Erratum: Nature 632: E2, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20962848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20962848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20962848[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/nature09459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20962848">Su et al. (2010)</a> found that modulation of expression of Dicer and miR130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. <a href="#50" class="mim-tip-reference" title="Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y.-L., Leung, M. L., El-Naggar, A., Creighton, C. J., Suraokar, M. B., Wistuba, I., Flores, E. R. <strong>TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.</strong> Nature 467: 986-990, 2010. Note: Erratum: Nature 632: E2, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20962848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20962848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20962848[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/nature09459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20962848">Su et al. (2010)</a> concluded that their data provided a novel understanding of the roles of TAp63 in tumor and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR130b, and may have implications for the many processes regulated by miRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20962848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RNA interference screening to identify targets of p63 in human keratinocytes, <a href="#9" class="mim-tip-reference" title="Borrelli, S., Candi, E., Hu, B., Dolfini, D., Ravo, M., Grober, O. M. V., Weisz, A., Dotto, G. P., Melino, G., Vigano, M. A., Mantovani, R. <strong>The p63 target HBP1 is required for skin differentiation and stratification.</strong> Cell Death Diff. 17: 1896-1907, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20523354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20523354</a>] [<a href="https://doi.org/10.1038/cdd.2010.59" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20523354">Borrelli et al. (2010)</a> showed that HBP1 (<a href="/entry/616714">616714</a>) was directly repressed by p63. Mice lacking p63 showed increased Hbp1 expression in keratinocytes. HBP1 was activated upon human keratinocyte differentiation and was required for keratinocyte stratification. <a href="#9" class="mim-tip-reference" title="Borrelli, S., Candi, E., Hu, B., Dolfini, D., Ravo, M., Grober, O. M. V., Weisz, A., Dotto, G. P., Melino, G., Vigano, M. A., Mantovani, R. <strong>The p63 target HBP1 is required for skin differentiation and stratification.</strong> Cell Death Diff. 17: 1896-1907, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20523354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20523354</a>] [<a href="https://doi.org/10.1038/cdd.2010.59" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20523354">Borrelli et al. (2010)</a> concluded that suppression of HBP1 enables p63-mediated growth promotion in the lower layers of epidermis and that HBP1 coordinates expression of genes involved in stratification, leading to formation of the skin barrier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20523354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Deutsch, G. B., Zielonka, E. M., Coutandin, D., Weber, T. A., Schafer, B., Hannewald, J., Luh, L. M., Durst, F. G., Ibrahim, M., Hoffmann, J., Niesen, F. H., Senturk, A., Kunkel, H., Brutschy, B., Schleiff, E., Knapp, S., Acker-Palmer, A., Grez, M., McKeon, F., Dotsch, V. <strong>DNA damage in oocytes induces a switch of the quality control factor TAp63-alpha from dimer to tetramer.</strong> Cell 144: 566-576, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21335238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21335238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21335238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2011.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21335238">Deutsch et al. (2011)</a> found that TAp63-alpha was maintained in a closed dimeric and inactive conformation in nonstressed murine oocytes. Phosphorylation opened the dimer and permitted formation of the active tetramer from 2 activated dimers. Dephosphorylation did not affect the oligomerization equilibrium. Mutation analysis showed that a helix within the oligomerization domain of TAp63-alpha was crucial for tetramer stabilization and essentially made the activation process irreversible. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21335238" 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 Western blot analysis of transfected 5637 human bladder cancer cells, <a href="#45" class="mim-tip-reference" title="Scheel, A. H. J., Beyer, U., Agami, R., Dobbelstein, M. <strong>Immunofluorescence-based screening identifies germ cell associated microRNA 302 as an antagonist to p63 expression.</strong> Cell Cycle 8: 1426-1432, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19342891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19342891</a>] [<a href="https://doi.org/10.4161/cc.8.9.8324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19342891">Scheel et al. (2009)</a> found that expression of a plasmid containing tandem sequences of all 4 MIR302 family members (see MIR302A; <a href="/entry/614596">614596</a>) and MIR367 (<a href="/entry/614600">614600</a>) downregulated p63 expression. Mutation analysis identified 2 functional MIR302 binding sites in the 3-prime UTR of the p63 transcript. Western blot analysis showed that transfection of GH testicular cancer cells with antagonizing oligonucleotides that blocked all MIR302 subspecies resulted in elevated p63 protein levels. RT-PCR confirmed that synthetic MIR302B (<a href="/entry/614597">614597</a>) downregulated p63 mRNA expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19342891" 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="Conforti, F., Yang, A. L., Piro, M. C., Mellone, M., Terrinoni, A., Candi, E., Tucci, P., Thomas, G. J., Knight, R. A., Melino, G., Sayan, B. S. <strong>PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21(WAF1) and p63.</strong> Oncogene 32: 4758-4765, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23128396/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23128396</a>] [<a href="https://doi.org/10.1038/onc.2012.497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23128396">Conforti et al. (2013)</a> identified the human E3 ubiquitin ligase PIR2 (RNF144B; <a href="/entry/618869">618869</a>) as a direct transcriptional target of p63 and found that PIR2 expression in keratinocytes and squamous cell carcinomas was predominantly dependent on p63. PIR2 depletion impaired proliferation of human epidermal keratinocytes. The authors found that PIR2 functioned downstream of p63 to regulate cell proliferation by mediating p21 (CDKN1A; <a href="/entry/116899">116899</a>) degradation. PIR2 depletion also impaired keratinocyte differentiation, as PIR2 expression was required for termination of differentiation in keratinocytes. Moreover, PIR2 depletion increased p63 protein level in keratinocytes, as p63 regulated its own protein level by transcriptionally activating PIR2, leading to p63 proteasomal degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23128396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse knockout models and transfected human cell lines, <a href="#40" class="mim-tip-reference" title="Restelli, M., Lopardo, T., Lo Iacono, N., Garaffo, G., Conte, D., Rustighi, A., Napoli, M., Del Sal, G., Perez-Morga, D., Costanzo, A., Merlo, G. R., Guerrini, L. <strong>DLX5, FGF8 and the Pin1 isomerase control delta-Np63-alpha protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations.</strong> Hum. Molec. Genet. 23: 3830-3842, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24569166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24569166</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24569166[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/10.1093/hmg/ddu096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24569166">Restelli et al. (2014)</a> found that DLX5 (<a href="/entry/600028">600028</a>) and TP63, which both can cause split hand/foot malformations when mutated, are involved in a regulatory loop during limb development. Proteasome-mediated degradation of delta-N p63-alpha was induced by the cis/trans isomerase PIN1 (<a href="/entry/601052">601052</a>). FGF8 (<a href="/entry/600483">600483</a>), a downstream DLX5 effector, countered delta-N p63-alpha degradation. <a href="#40" class="mim-tip-reference" title="Restelli, M., Lopardo, T., Lo Iacono, N., Garaffo, G., Conte, D., Rustighi, A., Napoli, M., Del Sal, G., Perez-Morga, D., Costanzo, A., Merlo, G. R., Guerrini, L. <strong>DLX5, FGF8 and the Pin1 isomerase control delta-Np63-alpha protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations.</strong> Hum. Molec. Genet. 23: 3830-3842, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24569166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24569166</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24569166[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/10.1093/hmg/ddu096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24569166">Restelli et al. (2014)</a> noted that both the Tp63 and Dlx5/Dlx6 (<a href="/entry/600030">600030</a>) mouse models of split hand/foot malformations show reduced Fgf8 expression in the apical ectodermal ridge. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24569166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#68" class="mim-tip-reference" title="Zuo, W., Zhang, T., Wu, D. Z., Guan, S. P., Liew, A.-A., Yamamoto, Y., Wang, X., Lim, S. J., Vincent, M., Lessard, M., Crum, C. P., Xian, W., McKeon, F. <strong>p63+Krt5+ distal airway stem cells are essential for lung regeneration.</strong> Nature 517: 616-620, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25383540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25383540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25383540[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/nature13903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25383540">Zuo et al. (2015)</a> showed that preexisting, intrinsically committed distal airway stem cells expressing TRP63 and keratin-5 (KRT5; <a href="/entry/148040">148040</a>), called DASC(p63/Krt5), undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. <a href="#68" class="mim-tip-reference" title="Zuo, W., Zhang, T., Wu, D. Z., Guan, S. P., Liew, A.-A., Yamamoto, Y., Wang, X., Lim, S. J., Vincent, M., Lessard, M., Crum, C. P., Xian, W., McKeon, F. <strong>p63+Krt5+ distal airway stem cells are essential for lung regeneration.</strong> Nature 517: 616-620, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25383540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25383540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25383540[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/nature13903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25383540">Zuo et al. (2015)</a> also showed that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to prefibrotic lesions and deficient oxygen exchange. Finally, the authors demonstrated that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. <a href="#68" class="mim-tip-reference" title="Zuo, W., Zhang, T., Wu, D. Z., Guan, S. P., Liew, A.-A., Yamamoto, Y., Wang, X., Lim, S. J., Vincent, M., Lessard, M., Crum, C. P., Xian, W., McKeon, F. <strong>p63+Krt5+ distal airway stem cells are essential for lung regeneration.</strong> Nature 517: 616-620, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25383540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25383540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25383540[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/nature13903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25383540">Zuo et al. (2015)</a> concluded that the ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25383540" 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="#60" class="mim-tip-reference" title="Vaughan, A. E., Brumwell, A. N., Xi, Y., Gotts, J. E., Brownfield, D. G., Treutlein, B., Tan, K., Tan, V., Liu, F. C., Looney, M. R., Matthay, M. A., Rock, J. R., Chapman, H. A. <strong>Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.</strong> Nature 517: 621-625, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533958</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533958[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/nature14112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25533958">Vaughan et al. (2015)</a> independently defined the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells that are present within normal distal lung. The authors stated that quiescent LNEPs activate a delta-Np63 (a p63 splice variant) and cytokeratin-5 (Krt5) remodeling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch (<a href="/entry/190198">190198</a>) signaling to activate the delta-Np63 and cytokeratin-5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signaling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signaling. <a href="#60" class="mim-tip-reference" title="Vaughan, A. E., Brumwell, A. N., Xi, Y., Gotts, J. E., Brownfield, D. G., Treutlein, B., Tan, K., Tan, V., Liu, F. C., Looney, M. R., Matthay, M. A., Rock, J. R., Chapman, H. A. <strong>Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury.</strong> Nature 517: 621-625, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533958</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533958[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/nature14112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25533958">Vaughan et al. (2015)</a> concluded that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and that the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25533958" 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>The delta-N isoforms (lacking the acidic transactivation domain) of p63 and p73 (<a href="/entry/601990">601990</a>) are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53 (<a href="/entry/191170">191170</a>), p63 bearing the acidic transactivation domain (TAp63), and TAp73 to inhibit their tumor-suppressive functions. <a href="#61" class="mim-tip-reference" title="Venkatanarayan, A., Raulji, P., Norton, W., Chakravarti, D., Coarfa, C., Su, X., Sandur, S. K., Ramirez, M. S., Lee, J., Kingsley, C. V., Sananikone, E. F., Rajapakshe, K., Naff, K., Parker-Thornburg, J., Bankson, J. A., Tsai, K. Y., Gunaratne, P. H., Flores, E. R. <strong>IAPP-driven metabolic reprogramming induces regression of p53-deficient tumors in vivo.</strong> Nature 517: 626-630, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25409149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25409149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25409149[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/nature13910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25409149">Venkatanarayan et al. (2015)</a> showed that deletion of the delta-N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumors through upregulation of IAPP (<a href="/entry/147940">147940</a>), the gene that encodes amylin, a 37-amino-acid peptide cosecreted with insulin by the beta cells of the pancreas. <a href="#61" class="mim-tip-reference" title="Venkatanarayan, A., Raulji, P., Norton, W., Chakravarti, D., Coarfa, C., Su, X., Sandur, S. K., Ramirez, M. S., Lee, J., Kingsley, C. V., Sananikone, E. F., Rajapakshe, K., Naff, K., Parker-Thornburg, J., Bankson, J. A., Tsai, K. Y., Gunaratne, P. H., Flores, E. R. <strong>IAPP-driven metabolic reprogramming induces regression of p53-deficient tumors in vivo.</strong> Nature 517: 626-630, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25409149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25409149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25409149[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/nature13910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25409149">Venkatanarayan et al. (2015)</a> found that IAPP is causally involved in tumor regression and that amylin functions through the calcitonin receptor (CALCR; <a href="/entry/114131">114131</a>) and RAMP3 (<a href="/entry/605155">605155</a>) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analog of amylin that is used to treat type 1 and type 2 diabetes, caused rapid tumor regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25409149" 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>Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome 3</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. <strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong> Cell 99: 143-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535733</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535733">Celli et al. (1999)</a> mapped EEC3 (<a href="/entry/604292">604292</a>), an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts, to a region of 3q27 where an EEC-like disorder, limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), had been mapped. Analysis of the p63 gene, which is located in the critical LMS/EEC3 interval, revealed heterozygous mutations in 9 unrelated EEC3 families. (see, e.g., <a href="#0001">603273.0001</a>-<a href="#0004">603273.0004</a>). Eight mutations resulted in amino acid substitutions that were predicted to abolish the DNA binding capacity of p63; the ninth was a frameshift mutation. Six of the 9 mutations were C-to-T transversions at CpG dinucleotides. Transactivation studies with these mutant p63 isotypes provided a molecular explanation for the dominant character of p63 mutations in EEC3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535733" 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>Split-Hand/Foot Malformation 4</em></strong></p><p>
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To assess the potential of p63 as a candidate gene for split-hand/foot malformation (SHFM4; <a href="/entry/605289">605289</a>), <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> analyzed the p63 gene in 2 multigenerational families with SHFM in which segregation analysis had excluded linkage to all previously identified autosomal regions. Two missense mutations, 724A-G in exon 5, which predicted a lys194-to-glu substitution (<a href="#0005">603273.0005</a>), and 982T-C in exon 7, which predicted an arg280-to-cys substitution (<a href="#0006">603273.0006</a>). <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> also identified mutations in the TP63 gene in families with EEC3; see <a href="#0007">603273.0007</a> and <a href="#0008">603273.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839977" 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>Ankyloblepharon-Ectodermal Defects-Clefting (AEC) Syndrome</em></strong></p><p>
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Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC; <a href="/entry/106260">106260</a>), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon, and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; <a href="/entry/604292">604292</a>), limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; <a href="/entry/103285">103285</a>), and recessive cleft lip/palate-ectodermal dysplasia (CLPED1; <a href="/entry/225060">225060</a>). <a href="#33" class="mim-tip-reference" title="McGrath, J. A., Duijf, P. H. G., Doetsch, V., Irvine, A. D., de Waal, R., Vanmolkot, K. R. J., Wessagowit, V., Kelly, A., Atherton, D. J., Griffiths, W. A. D., Orlow, S. J., van Haeringen, A., Ausems, M. G. E. M., Yang, A., McKeon, F., Bamshad, M. A., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.</strong> Hum. Molec. Genet. 10: 221-229, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159940</a>] [<a href="https://doi.org/10.1093/hmg/10.3.221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159940">McGrath et al. (2001)</a> analyzed the p63 gene in AEC syndrome patients and identified missense mutations in 8 families (see, e.g., <a href="#0009">603273.0009</a>-<a href="#0010">603273.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159940" 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 who displayed an overlapping phenotype with features of both AEC and Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#38" class="mim-tip-reference" title="Prontera, P., Escande, F., Cocchi, G., Donti, E., Martini, A., Sensi, A. <strong>An intermediate phenotype between Hays-Wells and Rapp-Hodgkin syndromes in a patient with a novel p63 mutation: confirmation of a variable phenotypic spectrum with a common aetiology.</strong> Genet. Counsel. 19: 397-402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19239083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19239083</a>]" pmid="19239083">Prontera et al. (2008)</a> identified heterozygosity for an 11-bp duplication in the TP63 gene (<a href="#0027">603273.0027</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19239083" 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="#41" class="mim-tip-reference" title="Rinne, T., Bolat, E., Meijer, R., Scheffer, H., van Bokhoven, H. <strong>Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC).</strong> Am. J. Med. Genet. 149A: 1948-1951, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19676060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19676060</a>] [<a href="https://doi.org/10.1002/ajmg.a.32793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19676060">Rinne et al. (2009)</a> analyzed the TP63 gene in 24 individuals from 12 different AEC families, and identified mutations in 21 of those tested; the 3 individuals without an identified mutation included 2 unaffected relatives and 1 patient with a phenotype slightly different than AEC/RHS. Of the 11 different mutations identified, 8 were within the coding region of the sterile alpha motif (SAM) domain, and 3 were located in the exon 14 sequence encoding the transactivation inhibitory (TI) domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19676060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using luciferase reporter assays, <a href="#5" class="mim-tip-reference" title="Beaudry, V. G., Pathak, N., Koster, M. I., Attardi, L. D. <strong>Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.</strong> Am. J. Med. Genet. 149A: 1952-1957, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19353588[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/10.1002/ajmg.a.32760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353588">Beaudry et al. (2009)</a> demonstrated compromise of PERP (<a href="/entry/609301">609301</a>) induction with some (see <a href="#0009">603273.0009</a>) but not all AEC-patient derived TP63 mutants. Skin biopsy analysis of AEC patients revealed a subset displaying aberrant PERP expression, suggesting that PERP dysregulation might be involved in the pathogenesis of this disease. <a href="#5" class="mim-tip-reference" title="Beaudry, V. G., Pathak, N., Koster, M. I., Attardi, L. D. <strong>Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.</strong> Am. J. Med. Genet. 149A: 1952-1957, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19353588[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/10.1002/ajmg.a.32760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353588">Beaudry et al. (2009)</a> concluded that distinct AEC TP63 mutants could differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using humanized mouse cDNAs expressed in regenerated human epidermal tissue and keratinocytes in culture, <a href="#66" class="mim-tip-reference" title="Zarnegar, B. J., Webster, D. E., Lopez-Pajares, V., Hunt, B. V. S., Qu, K., Yan, K. J., Berk, D. R., Sen, G. L., Khavari, P. A. <strong>Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63.</strong> Am. J. Hum. Genet. 91: 435-443, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22922031[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.2012.07.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922031">Zarnegar et al. (2012)</a> found that AEC-related mutations within the SAM domain of Tp63 repressed expression of transcriptional activators and markers of epidermal differentiation compared with wildtype Tp63. AEC-mutant Tp63 did not induce apoptosis or alter keratinocyte proliferation. ZNF750 (<a href="/entry/610226">610226</a>), KLF4 (<a href="/entry/602253">602253</a>), and GRHL3 (<a href="/entry/608317">608317</a>) were among a group of epidermal genes significantly downregulated by AEC-related mutations. Chromatin immunoprecipitation analysis and sequencing showed that both wildtype and AEC-mutant Tp63 bound 2 canonical TP63-binding sites near the ZNF750 transcriptional start site. Expression of exogenous ZNF750 in AEC model tissue rescued expression of the majority of TP63 target genes. Introduction of Tp63 variants lacking the SAM domain did not alter expression of epidermal differentiation markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22922031" 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 determining the NMR structure of the p63 SAM domain with the AEC-associated mutation L514F, followed by funtional analyses with L514F and other AEC-associated mutations, <a href="#44" class="mim-tip-reference" title="Russo, C., Osterburg, C., Sirico, A., Antonini, D., Ambrosio, R., Wurz, J. M., Rinnenthal, J., Ferniani, M., Kehrloesser, S., Schafer, B., Guntert, P., Sinha, S., Dotsch, V., Missero, C. <strong>Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome.</strong> Proc. Nat. Acad. Sci. 115: E906-E915, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29339502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29339502</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29339502[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.1713773115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29339502">Russo et al. (2018)</a> showed that AEC mutations destabilized the SAM domain, leading to aggregation of the p63 protein. Moreover, AEC-associated p63 mutants not only caused aggregation of wildtype p63, but they also selectively bound other p53 family members and caused their aggregation. In vitro analysis and in vivo analysis of a mouse AEC model revealed that p63 aggregation impaired both the transactivation and repression functions of p63, as aggregated p63 mutant proteins had weakened ability to bind DNA. Reducing the aggregation propensity of AEC-associated mutant p63 proteins restored their transcriptional activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29339502" 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>ADULT Syndrome</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T. <strong>TP63 gene mutation in ADULT syndrome.</strong> Europ. J. Hum. Genet. 9: 642-645, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528512</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200676" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528512">Amiel et al. (2001)</a> reported a missense mutation (<a href="#0011">603273.0011</a>) in the TP63 gene in an isolated case of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (<a href="/entry/103285">103285</a>), which maps to chromosome 3q27. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome. <a href="#2" class="mim-tip-reference" title="Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T. <strong>TP63 gene mutation in ADULT syndrome.</strong> Europ. J. Hum. Genet. 9: 642-645, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528512</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200676" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528512">Amiel et al. (2001)</a> considered incomplete penetrance as the most likely explanation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528512" 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 affected members of a 2-generation family with ADULT syndrome, <a href="#17" class="mim-tip-reference" title="Duijf, P. H. G., Vanmolkot, K. R. J., Propping, P., Friedl, W., Krieger, E., McKeon, F., Dotsch, V., Brunner, H. G., van Bokhoven, H. <strong>Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63.</strong> Hum. Molec. Genet. 11: 799-804, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929852</a>] [<a href="https://doi.org/10.1093/hmg/11.7.799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11929852">Duijf et al. (2002)</a> identified a heterozygous mutation in the TP63 gene (R298Q; <a href="#0014">603273.0014</a>). <a href="#42" class="mim-tip-reference" title="Rinne, T., Hamel, B., van Bokhoven, H., Brunner, H. G. <strong>Pattern of p63 mutations and their phenotypes--update.</strong> Am. J. Med. Genet. 140A: 1396-1406, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691622</a>] [<a href="https://doi.org/10.1002/ajmg.a.31271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16691622">Rinne et al. (2006)</a> identified the R298Q mutation in affected members of 2 unrelated families with ADULT syndrome; 1 was Italian, and the other was Dutch. A third family of Finnish origin had a different mutation at the same codon (R298G; <a href="#0022">603273.0022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16691622+11929852" 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 Dutch mother and daughter with minimal manifestations of ADULT syndrome, including hypothelia and palmar hyperlinearity, <a href="#59" class="mim-tip-reference" title="van Zelst-Stams, W. A. G., van Steensel, M. A. M. <strong>A novel TP63 mutation in a family with ADULT syndrome presenting with eczema and hypothelia. (Letter)</strong> Am. J. Med. Genet. 149A: 1558-1560, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19530185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19530185</a>] [<a href="https://doi.org/10.1002/ajmg.a.32881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19530185">van Zelst-Stams and van Steensel (2009)</a> identified heterozygosity for a missense mutation in the C-terminal end of the proline-rich domain of TP63 (P127L; <a href="#0026">603273.0026</a>). The authors stated that mutations in this domain have primarily been reported to cause limb-mammary syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19530185" 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 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular dysplasia, who did not have the skin and limb manifestations of ADULT syndrome, <a href="#56" class="mim-tip-reference" title="Valenzise, M., Arrigo, T., De Luca, F., Privitera, A., Frigiola, A., Carando, A., Garelli, E., Silengo, M. <strong>R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy. (Letter)</strong> Europ. J. Med. Genet. 51: 497-500, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18603493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18603493</a>] [<a href="https://doi.org/10.1016/j.ejmg.2008.05.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18603493">Valenzise et al. (2008)</a> identified the R298Q mutation in the TP63 gene. The mutation was also found in his mother, who displayed only hypodontia and athelia. <a href="#56" class="mim-tip-reference" title="Valenzise, M., Arrigo, T., De Luca, F., Privitera, A., Frigiola, A., Carando, A., Garelli, E., Silengo, M. <strong>R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy. (Letter)</strong> Europ. J. Med. Genet. 51: 497-500, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18603493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18603493</a>] [<a href="https://doi.org/10.1016/j.ejmg.2008.05.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18603493">Valenzise et al. (2008)</a> noted that their findings highlighted the clinical overlapping of TP63-related ectodermal dysplasias and the difficulty of establishing unequivocal genotype-phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18603493" 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>Limb-Mammary Syndrome</em></strong></p><p>
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In 2 unrelated patients with limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al. (2001)</a> sequenced the TP63 gene and identified heterozygosity for 2 different frameshift mutations: a 2-bp deletion in exon 13 (<a href="#0012">603273.0012</a>) and a 2-bp deletion in exon 14 (<a href="#0013">603273.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11462173" 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 affected members of a Danish family with features of LMS but without limb anomalies, <a href="#32" class="mim-tip-reference" title="Mathorne, S. W., Ravn, P., Hansen, D., Beck-Nielsen, S. S., Gjorup, H., Sorensen, K. P., Fagerberg, C. R. <strong>Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect.</strong> Clin. Genet. 97: 779-784, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32067224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32067224</a>] [<a href="https://doi.org/10.1111/cge.13725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32067224">Mathorne et al. (2020)</a> identified heterozygosity for a nonsense mutation in the TP63 gene (R643X; <a href="#0035">603273.0035</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32067224" 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>Rapp-Hodgkin Syndrome</em></strong></p><p>
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In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#25" class="mim-tip-reference" title="Kantaputra, P. N., Hamada, T., Kumchai, T., McGrath, J. A. <strong>Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia.</strong> J. Dent. Res. 82: 433-437, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12766194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12766194</a>] [<a href="https://doi.org/10.1177/154405910308200606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12766194">Kantaputra et al. (2003)</a> identified heterozygosity for a missense mutation (S545P; <a href="#0019">603273.0019</a>) in the TP73L gene. <a href="#25" class="mim-tip-reference" title="Kantaputra, P. N., Hamada, T., Kumchai, T., McGrath, J. A. <strong>Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia.</strong> J. Dent. Res. 82: 433-437, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12766194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12766194</a>] [<a href="https://doi.org/10.1177/154405910308200606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12766194">Kantaputra et al. (2003)</a> stated that this was the first genetic abnormality to be described in RHS, and noted that this provides molecular data to support the clinically observed overlap between EEC, AEC, and RHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12766194" 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 mother and daughter with RHS associated with corneal dystrophy and premature menopause, <a href="#22" class="mim-tip-reference" title="Holder-Espinasse, M., Martin-Coignard, D., Escande, F., Manouvrier-Hanu, S. <strong>A new mutation in TP63 is associated with age-related pathology.</strong> Europ. J. Hum. Genet. 15: 1115-1120, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17609671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17609671</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17609671">Holder-Espinasse et al. (2007)</a> identified heterozygosity for a 1-bp deletion in the TP73L gene (<a href="#0025">603273.0025</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17609671" 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 who displayed an overlapping phenotype with features of both AEC and RHS, <a href="#38" class="mim-tip-reference" title="Prontera, P., Escande, F., Cocchi, G., Donti, E., Martini, A., Sensi, A. <strong>An intermediate phenotype between Hays-Wells and Rapp-Hodgkin syndromes in a patient with a novel p63 mutation: confirmation of a variable phenotypic spectrum with a common aetiology.</strong> Genet. Counsel. 19: 397-402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19239083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19239083</a>]" pmid="19239083">Prontera et al. (2008)</a> identified heterozygosity for an 11-bp duplication in the TP63 gene (<a href="#0027">603273.0027</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19239083" 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>Orofacial Cleft 8</em></strong></p><p>
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Because mutations in the TP63 gene underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate, <a href="#28" class="mim-tip-reference" title="Leoyklang, P., Siriwan, P., Shotelersuk, V. <strong>A mutation of the p63 gene in non-syndromic cleft lip. (Letter)</strong> J. Med. Genet. 43: e28, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740912[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.036442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16740912">Leoyklang et al. (2006)</a> performed mutation analysis of the 16 exons of the gene in 100 Thai patients with nonsyndromic CL/P (OFC8; <a href="/entry/618149">618149</a>). In total, 21 single nucleotide changes were found, of which 6 were in the coding regions, including 3 novel nonsynonymous changes: S90L, R313G (<a href="#0021">603273.0021</a>), and D564H. The R313G change was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, occurrence in a functionally important domain, predicted damaging function, de novo occurrence, and its absence in 500 control individuals. The finding highlighted further the wide phenotypic spectrum of TP63 gene mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16740912" 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 family (CLP-1055) in which the proband and his father had orofacial cleft-8, <a href="#4" class="mim-tip-reference" title="Basha, M., Demeer, B., Revencu, N., Helaers, R., Theys, S., Saba, S. B., Boute, O., Devauchelle, B., Francois, G., Bayet, B., Vikkula, M. <strong>Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes.</strong> J. Med. Genet. 55: 449-458, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29500247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29500247</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-105110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29500247">Basha et al. (2018)</a> identified heterozygosity for a 2-bp duplication (<a href="#0029">603273.0029</a>) in the TP63 gene. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. Neither patient had any symptoms of other TP63 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29500247" 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>Premature Ovarian Failure 21</em></strong></p><p>
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In 2 unrelated women with isolated primary amenorrhea (POF21; <a href="/entry/620311">620311</a>) who were negative for mutation in known POF-associated genes, <a href="#55" class="mim-tip-reference" title="Tucker, E. J., Jaillard, S., Grover, S. R., van den Bergen, J., Robevska, G., Bell, K. M., Sadedin, S., Hanna, C., Dulon, J., Touraine, P., Sinclair, A. H. <strong>TP63-truncating variants cause isolated premature ovarian insufficiency.</strong> Hum. Mutat. 40: 886-892, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30924587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30924587</a>] [<a href="https://doi.org/10.1002/humu.23744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30924587">Tucker et al. (2019)</a> identified heterozygosity for 2 different nonsense mutations in the last exon (exon 14) of the TP63 gene, R594X (<a href="#0030">603273.0030</a>) and W598X (<a href="#0031">603273.0031</a>). In the family for which parental DNA was available, the mutation was shown to have arisen de novo; neither mutation was found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30924587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated women with premature ovarian failure, <a href="#54" class="mim-tip-reference" title="Tucker, E. J., Gutfreund, N., Belaud-Rotureau, M. A., Gilot, D., Brun, T., Kline, B. L., Bell, K. M., Domin-Bernhard, M., Theard, C., Touraine, P., Robevska, G., van van den Bergen, J., Ayers, K. L., Sinclair, A. H., Dotsch, V., Jaillard, S. <strong>Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.</strong> Hum. Mutat. 43: 1443-1453, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35801529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35801529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35801529[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/10.1002/humu.24432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35801529">Tucker et al. (2022)</a> identified heterozygosity for missense mutations in the TP63 gene, including R97P (<a href="#0032">603273.0032</a>) and R647C (<a href="#0033">603273.0033</a>), which were shown to disrupt TP63 dimerization, causing an open active tetramer conformation with a significant increase in transcriptional activity. The third variant, Y18C, had no detectable impact on conformation or transcriptional activity. <a href="#54" class="mim-tip-reference" title="Tucker, E. J., Gutfreund, N., Belaud-Rotureau, M. A., Gilot, D., Brun, T., Kline, B. L., Bell, K. M., Domin-Bernhard, M., Theard, C., Touraine, P., Robevska, G., van van den Bergen, J., Ayers, K. L., Sinclair, A. H., Dotsch, V., Jaillard, S. <strong>Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.</strong> Hum. Mutat. 43: 1443-1453, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35801529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35801529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35801529[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/10.1002/humu.24432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35801529">Tucker et al. (2022)</a> suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35801529" 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="Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S. <strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong> J. Clin. Invest. 133: e162315, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36856110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36856110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36856110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI162315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36856110">Huang et al. (2023)</a> analyzed WES data from a cohort of 1,030 Chinese women diagnosed with premature ovarian insufficiency, and identified 8 unrelated Chinese women with heterozygous mutations in the TP63 gene, including 3 with secondary amenorrhea and the previously reported R647C mutation, and 1 with primary amenorrhea and the R594X mutation. All but 1 of the mutations were in exon 14; patient 4, who had primary amenorrhea, was heterozygous for a 1-bp deletion in exon 13 (<a href="#0034">603273.0034</a>). The mutations were confirmed by Sanger sequencing and were either not found or were present at low minor allele frequency in the ExAC and/or gnomAD databases. Functional analysis suggested that variants affecting the C-terminal transactivation-inhibitory domain disrupt the inactive TP63 conformation, generating constitutively active TAp63-alpha that increases expression of target genes and induces apoptosis, thus causing exhaustion of oocytes that results in premature ovarian failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36856110" 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>Functional Effects of p63 Mutations</em></strong></p><p>
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Using mouse models, <a href="#29" class="mim-tip-reference" title="Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E., Mills, A. A., Morasso, M. I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G. R. <strong>Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.</strong> Development 135: 1377-1388, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326838</a>] [<a href="https://doi.org/10.1242/dev.011759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18326838">Lo Iacono et al. (2008)</a> found that p63 mutations associated with split-hand/foot malformation (e.g., K194E; <a href="#0005">603273.0005</a>) and ectrodactyly-ectodermal dysplasia-cleft lip (e.g., R279H; <a href="#0007">603273.0007</a>), which lie within the DNA-binding domain of p63, reduced the ability of p63 to activate DLX5 (<a href="/entry/600028">600028</a>) and DLX6 (<a href="/entry/600030">600030</a>) promoter reporter constructs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18326838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the TP63 gene and lung cancer, see <a href="/entry/614210">614210</a>.</p><p>For discussion of a possible association between homozygosity or heterozygosity for a rare TP63 insertion polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34201045;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs34201045</a>) and SHFM caused by mutation in the WNT10B gene (<a href="/entry/601906">601906</a>), see SHFM6 (<a href="/entry/225300">225300</a>).</p>
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<p><a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> identified 4 TP63 mutations in patients with SHFM4 and EEC3. All 4 mutations were found in exons that fall within the DNA-binding domain of p63. The 2 amino acids mutated in the families with SHFM appeared to be involved primarily in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="McGrath, J. A., Duijf, P. H. G., Doetsch, V., Irvine, A. D., de Waal, R., Vanmolkot, K. R. J., Wessagowit, V., Kelly, A., Atherton, D. J., Griffiths, W. A. D., Orlow, S. J., van Haeringen, A., Ausems, M. G. E. M., Yang, A., McKeon, F., Bamshad, M. A., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.</strong> Hum. Molec. Genet. 10: 221-229, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159940</a>] [<a href="https://doi.org/10.1093/hmg/10.3.221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159940">McGrath et al. (2001)</a> noted that p63 mutations resulting in the AEC syndrome result in amino acid substitutions in the sterile alpha motif (SAM) domain and are predicted to affect protein-protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. The authors suggested that a distinct genotype-phenotype correlation can be recognized for EEC and AEC syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="van Bokhoven, H., Brunner, H. G. <strong>Splitting p63.</strong> Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12037717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12037717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12037717[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/10.1086/341450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12037717">Van Bokhoven and Brunner (2002)</a> reviewed the spectrum of p63 mutations underlying 5 human malformation syndromes. Clustering of mutations established a clear genotype-phenotype correlation: in the DNA binding domain (DBD) for EEC syndrome and in the SAM domain for AEC syndrome. Limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>) differs from EEC syndrome in at least 3 respects: (1) mammary gland and nipple hypoplasia are consistent features of LMS but are only occasionally seen in EEC syndrome; (2) patients with LMS do not have the hair and skin defects that are seen in EEC syndrome; (3) whereas patients with LMS have cleft palate, those with EEC syndrome have cleft lip/palate but never have cleft palate only. Phenotypically, LMS is most similar to ADULT syndrome. Two isolated patients with an LMS phenotype had, in exons 13 and 14, frameshift mutations that resulted in truncation of the p63-alpha protein. Therefore, the abundant p63 product in epithelial cells would be missing the transactivation inhibitory domain (TID). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12037717" 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="#11" class="mim-tip-reference" title="Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>P63 gene mutations and human developmental syndromes.</strong> Am. J. Med. Genet. 112: 284-290, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12357472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12357472</a>] [<a href="https://doi.org/10.1002/ajmg.10778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12357472">Brunner et al. (2002)</a> reviewed p63 mutations causing developmental syndromes. They stated that the pattern of heterozygous mutations is distinct for each syndrome, and that consistent with this syndrome-specific mutation pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12357472" 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="#42" class="mim-tip-reference" title="Rinne, T., Hamel, B., van Bokhoven, H., Brunner, H. G. <strong>Pattern of p63 mutations and their phenotypes--update.</strong> Am. J. Med. Genet. 140A: 1396-1406, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16691622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16691622</a>] [<a href="https://doi.org/10.1002/ajmg.a.31271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16691622">Rinne et al. (2006)</a> reviewed the clinical features of 227 patients with p63 mutations and detailed the variable phenotypic features associated with 5 mutation hotspots, which are all C-T transitions at CpG islands (see <a href="#0001">603273.0001</a>; <a href="#0006">603273.0006</a>-<a href="#0008">603273.0008</a>; <a href="#0024">603273.0024</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16691622" 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 affected members of 2 unrelated families with EEC syndrome, features of LMS, and severe micturition difficulties, <a href="#31" class="mim-tip-reference" title="Maclean, K., Holme, S. A., Gilmour, E., Taylor, M., Scheffer, H., Graf, N., Smith, G. H. H., Onikul, E., van Bokhoven, H., Moss, C., Ades, L. C. <strong>EEC syndrome, arg227-to-gln TP63 mutation and micturition difficulties: is there a genotype-phenotype correlation?</strong> Am. J. Med. Genet. 143A: 1114-1119, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431922</a>] [<a href="https://doi.org/10.1002/ajmg.a.31664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431922">Maclean et al. (2007)</a> identified the R227Q mutation in the TP73L gene (<a href="#0024">603273.0024</a>). The authors stated that 4 of the 6 cases/families reported with EEC and the R227Q mutation have manifested this distinct urologic abnormality (see <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al., 2001</a>), indicative of a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11462173+17431922" 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="#64" class="mim-tip-reference" title="Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C., McKeon, F. <strong>p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.</strong> Nature 398: 714-718, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227294</a>] [<a href="https://doi.org/10.1038/19539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10227294">Yang et al. (1999)</a> generated mice deficient in p63 by targeted disruption. p63 -/- mice have major defects in their limb, craniofacial, and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches, and epidermal appendages, which are all sites of reciprocal signaling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge (AER), which is essential for limb development. The embryonic epidermis of p63 -/- mice undergoes an unusual process of nonregenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrimal, and salivary glands. <a href="#64" class="mim-tip-reference" title="Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C., McKeon, F. <strong>p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.</strong> Nature 398: 714-718, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227294</a>] [<a href="https://doi.org/10.1038/19539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10227294">Yang et al. (1999)</a> concluded that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10227294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Mills, A. A., Zheng, B., Wang, X. J., Vogel, H., Roop, D. R., Bradley, A. <strong>p63 is a p53 homologue required for limb and epidermal morphogenesis.</strong> Nature 398: 708-713, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227293</a>] [<a href="https://doi.org/10.1038/19531" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10227293">Mills et al. (1999)</a> independently generated mice deficient in p63. The p63-deficient mice were born alive but had striking developmental defects. Their limbs were absent or truncated, defects that were caused by a failure of the AER to differentiate. The skin of p63-deficient mice did not progress past an early developmental stage: it lacked stratification and did not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth, and mammary glands, were absent in p63-deficient mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10227293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Keyes, W. M., Vogel, H., Koster, M. I., Guo, X., Qi, Y., Petherbridge, K. M., Roop, D. R., Bradley, A., Mills, A. A. <strong>p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors.</strong> Proc. Nat. Acad. Sci. 103: 8435-8440, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16714381[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.0602477103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714381">Keyes et al. (2006)</a> studied spontaneous tumorigenesis in p63 +/- mice in both wildtype and p53-compromised backgrounds. p63 +/- mice were not tumor prone, and mice heterozygous for both p63 and p53 had fewer tumors than p53 +/- mice. The rare tumors that developed in mice with compromised p63 were distinct from those of p53 +/- mice. Furthermore, p63 +/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. <a href="#26" class="mim-tip-reference" title="Keyes, W. M., Vogel, H., Koster, M. I., Guo, X., Qi, Y., Petherbridge, K. M., Roop, D. R., Bradley, A., Mills, A. A. <strong>p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors.</strong> Proc. Nat. Acad. Sci. 103: 8435-8440, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16714381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16714381</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16714381[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.0602477103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16714381">Keyes et al. (2006)</a> concluded that p63 plays a markedly different role in tumor formation than p53. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16714381" 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="#52" class="mim-tip-reference" title="Suzuki, K., Haraguchi, R., Ogata, T., Barbieri, O., Alegria, O., Vieux-Rochas, M., Nakagata, N., Ito, M., Mills, A. A., Kurita, T., Levi, G., Yamada, G. <strong>Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4.</strong> Europ. J. Hum. Genet. 16: 36-44, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17878916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17878916</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17878916">Suzuki et al. (2008)</a> showed that Dlx5 (<a href="/entry/600028">600028</a>), Dlx6 (<a href="/entry/600030">600030</a>), p63, and Bmp7 (<a href="/entry/112267">112267</a>), a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17878916" 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>The AER is a transitory multilayered ectoderm acting as a signaling center essential for distal limb development and digit patterning. <a href="#29" class="mim-tip-reference" title="Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E., Mills, A. A., Morasso, M. I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G. R. <strong>Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.</strong> Development 135: 1377-1388, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18326838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18326838</a>] [<a href="https://doi.org/10.1242/dev.011759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18326838">Lo Iacono et al. (2008)</a> stated that the normal stratified organization of the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6 double-knockout limbs. They found that p63 colocalized with Dlx5 and Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5 and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63 isoform expressed in developing limbs. Delta-N p63-alpha bound and activated transcription of Dlx5 and Dlx6 reporter constructs. Other delta-N isoforms were less active, and isoforms containing the N-terminal transactivation domain showed no activity with Dlx5 and Dlx6 reporters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18326838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y.-L., Leung, M. L., El-Naggar, A., Creighton, C. J., Suraokar, M. B., Wistuba, I., Flores, E. R. <strong>TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.</strong> Nature 467: 986-990, 2010. Note: Erratum: Nature 632: E2, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20962848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20962848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20962848[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/nature09459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20962848">Su et al. (2010)</a> generated mice lacking TAp63. In 2.5 years of study, both heterozygous and TAp63-null mice developed spontaneous carcinomas and sarcomas and had a significantly shorter life span than the wildtype cohort. Paradoxically, a larger proportion of TAp63-null mice (24%) were tumor-free compared with TAp63 heterozygous mice (15%). <a href="#50" class="mim-tip-reference" title="Su, X., Chakravarti, D., Cho, M. S., Liu, L., Gi, Y. J., Lin, Y.-L., Leung, M. L., El-Naggar, A., Creighton, C. J., Suraokar, M. B., Wistuba, I., Flores, E. R. <strong>TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.</strong> Nature 467: 986-990, 2010. Note: Erratum: Nature 632: E2, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20962848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20962848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20962848[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/nature09459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20962848">Su et al. (2010)</a> concluded that their data suggested that TAp63 is a haploinsufficient tumor suppressor gene. Consistent with this finding, sarcomas and carcinomas from TAp63 heterozygous mice retained the wildtype allele of TAp63. TAp63 heterozygous and null mice developed highly metastatic tumors and 10% of these metastases were found in the brain, a rare finding in spontaneous mouse tumor models. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20962848" 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="Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S. <strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong> J. Clin. Invest. 133: e162315, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36856110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36856110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36856110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI162315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36856110">Huang et al. (2023)</a> generated mice with a stop codon prior to the TID in exon 14 of the p63 gene, selectively altering the oocyte-specific p63-alpha isoform. Heterozygous mutant females were infertile, whereas mutant males were fertile. Ovary size in the mutant female mice was markedly reduced, and the number of follicles was substantially reduced at postnatal day 1 (P1), with follicles completely absent by P21. Oocyte numbers were reduced to approximately 40% of those of wildtype mice, and had completely disappeared by P10. The mutant females showed elevated FSH and decreased estradiol levels. The authors suggested that expression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype. Immunofluorescence staining of P1 ovarian sections showed a significant increase in cleaved-PARP1 (<a href="/entry/173870">173870</a>)-positive oocytes in mutant ovaries compared to wildtype. Increased expression of Bax (<a href="/entry/600040">600040</a>), Puma (BBC3; <a href="/entry/605854">605854</a>), and Noxa (PMAIP1; <a href="/entry/604959">604959</a>) was observed, suggesting that deleting the TID of the p63 protein was sufficient to induce uncontrolled apoptosis of oocytes in primordial follicles without exogenous damage. In vitro analysis in SAOS-2 cells confirmed that activated p63 lacking the TID triggers downstream proapoptotic pathways, causing oocyte exhaustion and infertility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36856110" 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 3 unrelated patients with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#12" class="mim-tip-reference" title="Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. <strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong> Cell 99: 143-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535733</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535733">Celli et al. (1999)</a> identified a heterozygous arg204-to-trp (R204W) mutation in the DNA binding domain of TP63. The mutation segregated with the disease in 2 families and was not found in normal controls. In the third family, the mutation occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Kosaki, R., Naito, Y., Torii, C., Takahashi, T., Nakajima, T., Kosaki, K. <strong>Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation. (Letter)</strong> Am. J. Med. Genet. 146A: 2574-2577, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18792980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18792980</a>] [<a href="https://doi.org/10.1002/ajmg.a.32415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18792980">Kosaki et al. (2008)</a> reported a Japanese male infant with EEC3 who was found to be heterozygous for the R204W mutation. He had a classic phenotype with split hand-foot malformation and cleft lip and palate. His father, who was found to be somatic mosaic for the mutation, had split hand-foot malformation, no cleft lip or palate, and whorl-like streaky pigmentary patterns of the skin following Blaschko lines. He had gray hair on the right half of his scalp and brown thin hair on the left side. He also had enamel hypoplasia and partial anodontia. Extensive genetic analysis demonstrated that the father was mosaic for the mutation in peripheral blood and hair, although most of his sperm carried the mutation. <a href="#27" class="mim-tip-reference" title="Kosaki, R., Naito, Y., Torii, C., Takahashi, T., Nakajima, T., Kosaki, K. <strong>Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation. (Letter)</strong> Am. J. Med. Genet. 146A: 2574-2577, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18792980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18792980</a>] [<a href="https://doi.org/10.1002/ajmg.a.32415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18792980">Kosaki et al. (2008)</a> concluded that the mutation was postzygotic in the father and resulted in gonosomal mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18792980" 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">rs121908836 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908836;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=rs121908836" 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=rs121908836" 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=RCV000006901 OR RCV000705452 OR RCV001804714 OR RCV002250454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006901, RCV000705452, RCV001804714, RCV002250454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006901...</a>
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<p>In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#12" class="mim-tip-reference" title="Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. <strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong> Cell 99: 143-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535733</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535733">Celli et al. (1999)</a> identified a heterozygous arg204-to-gln mutation in the core element II of the DNA binding domain of TP63. The mutation segregated with the disease and was not found in normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908837 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908837;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=rs121908837" 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=rs121908837" 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=RCV000006902" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006902" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006902</a>
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<p>In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#12" class="mim-tip-reference" title="Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. <strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong> Cell 99: 143-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535733</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535733">Celli et al. (1999)</a> identified a heterozygous cys306-to-arg mutation in the core element IV of the DNA binding domain of TP63. The mutation was de novo and was not found in normal controls. Transactivation assays using cell lysates containing the cys306-to-arg mutation showed a total lack of transactivation activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535733" 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 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108864810 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108864810;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=rs2108864810" 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=rs2108864810" 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=RCV000006903" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006903" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006903</a>
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<p>In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#12" class="mim-tip-reference" title="Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. <strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong> Cell 99: 143-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10535733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10535733</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10535733">Celli et al. (1999)</a> identified a 1-bp insertion (A) at nucleotide 1572 in exon 13 of the TP63 gene, resulting in a frameshift at codon 525 (tyr) and a premature stop codon in the same exon. The mutation was de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10535733" 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 SPLIT-HAND/FOOT MALFORMATION 4</strong>
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TP63, LYS194GLU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908838 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908838;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=rs121908838" 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=rs121908838" 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=RCV000006904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006904</a>
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<p>In a family with split-hand/foot malformation (SHFM4; <a href="/entry/605289">605289</a>) from South Africa, previously reported by <a href="#48" class="mim-tip-reference" title="Spranger, M., Schapera, J. <strong>Anomalous inheritance in a kindred with split hand, split foot malformation.</strong> Europ. J. Pediat. 147: 202-205, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3366140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3366140</a>] [<a href="https://doi.org/10.1007/BF00442225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3366140">Spranger and Schapera (1988)</a>, <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> identified a 724A-G transition in exon 5 of the p63 gene, predicted to cause a lys194-to-glu (K194E) amino acid substitution. This family, designated R, was of mixed ancestry from Cape Province. The spectrum of clinical manifestations was broad, ranging from the presence of a split hand in 1 individual to bilateral monodactyly and unilateral aplasia of the right lower extremity with a split left foot in another individual. No family members had any significant abnormalities other than those of the extremities. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3366140+10839977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 SPLIT-HAND/FOOT MALFORMATION 4</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">rs121908839 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908839;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=rs121908839" 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=rs121908839" 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=RCV000006905 OR RCV001280776 OR RCV002512857 OR RCV003162215" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006905, RCV001280776, RCV002512857, RCV003162215" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006905...</a>
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<p>In a family of mixed ancestry from Cape Province, South Africa, with split-hand/foot malformation (SHFM4; <a href="/entry/605289">605289</a>), <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> identified a 982T-C transition in exon 7 of the TP63 gene, predicted to cause an arg280-to-cys (R280C) amino acid substitution. The phenotype in this family, designated A, ranged from severe 'lobster claw' malformations of the feet in 1 individual, to minor 3/4 syndactyly of the left foot appearing as the only manifestation in another individual. The daughter of the latter individual had distal duplications of her thumbs bilaterally with absence of the second and third phalanges of the right hand and an absent second phalanx with 3/4 syndactyly of the left hand. No members of the family had significant abnormality of the face, palate, skin, teeth, hair, or nails. No abnormalities of the mammary glands or nipples were noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839977" 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 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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RAPP-HODGKIN SYNDROME, INCLUDED
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TP63, ARG279HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908840;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=rs121908840" 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=rs121908840" 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=RCV000006906 OR RCV000006907 OR RCV000478736 OR RCV000548176" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006906, RCV000006907, RCV000478736, RCV000548176" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006906...</a>
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<p><strong><em>Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome</em></strong></p><p>
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In a study of 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H) substitution, and a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution (<a href="#0008">603273.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839977" 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>Rapp-Hodgkin Syndrome</em></strong></p><p>
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In a 25-year-old female with features consistent with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#10" class="mim-tip-reference" title="Bougeard, G., Hadj-Rabia, S., Faivre, L., Sarafan-Vasseur, N., Frebourg, T. <strong>The Rapp-Hodgkin syndrome results from mutations of the TP63 gene.</strong> Europ. J. Hum. Genet. 11: 700-704, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939657</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939657">Bougeard et al. (2003)</a> identified heterozygosity for the R279H substitution. This residue corresponds to the R248 hotspot mutation in TP53 (see <a href="/entry/191170">191170</a>), and occurs within the DNA-binding domain present within all of the TP63 isoforms. In vitro functional analysis showed that this mutation did not decrease the transcriptional activity of the TAp63-gamma isoform on a TP53 reporter system, but disrupted the dominant-negative activity of the delta-N-p63-alpha and -gamma isoforms on the transcriptional activity of TP53. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908841;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=rs121908841" 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=rs121908841" 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=RCV000006908 OR RCV000276670 OR RCV000655484 OR RCV001266717 OR RCV005025018" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006908, RCV000276670, RCV000655484, RCV001266717, RCV005025018" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006908...</a>
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<p>In a study of 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#24" class="mim-tip-reference" title="Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. <strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong> Am. J. Hum. Genet. 67: 59-66, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839977</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10839977[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/10.1086/302972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839977">Ianakiev et al. (2000)</a> identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution, and a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H; <a href="#0007">603273.0007</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE</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">rs121908842 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908842;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=rs121908842" 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=rs121908842" 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=RCV000006909" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006909" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006909</a>
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<p>In a 6-year-old patient with Hay-Wells syndrome (AEC; <a href="/entry/106260">106260</a>) who lacked any limb defects, <a href="#33" class="mim-tip-reference" title="McGrath, J. A., Duijf, P. H. G., Doetsch, V., Irvine, A. D., de Waal, R., Vanmolkot, K. R. J., Wessagowit, V., Kelly, A., Atherton, D. J., Griffiths, W. A. D., Orlow, S. J., van Haeringen, A., Ausems, M. G. E. M., Yang, A., McKeon, F., Bamshad, M. A., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.</strong> Hum. Molec. Genet. 10: 221-229, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159940</a>] [<a href="https://doi.org/10.1093/hmg/10.3.221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159940">McGrath et al. (2001)</a> identified an A-to-T transversion at nucleotide 1542 of the TP63 gene, resulting in a leu518-to-phe substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a>, this mutation is designated leu514 to phe. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11159940+9774969" 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 transactivation assay, <a href="#5" class="mim-tip-reference" title="Beaudry, V. G., Pathak, N., Koster, M. I., Attardi, L. D. <strong>Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.</strong> Am. J. Med. Genet. 149A: 1952-1957, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19353588[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/10.1002/ajmg.a.32760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19353588">Beaudry et al. (2009)</a> demonstrated that TA-TP63-alpha-L514F was completely defective in activating the PERP (<a href="/entry/609301">609301</a>) luciferase reporter compared to wildtype. The authors hypothesized that specific protein-protein interactions needed for full PERP transactivation by TP63 are abolished when the structure of the sterile alpha motif (SAM) domain is compromised, as is the case with the L514F mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353588" 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">rs121908843 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908843;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=rs121908843" 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=rs121908843" 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=RCV000006910 OR RCV001067605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006910, RCV001067605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006910...</a>
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<p>In a 10-month-old infant with typical features of Hay-Wells syndrome (AEC; <a href="/entry/106260">106260</a>), <a href="#33" class="mim-tip-reference" title="McGrath, J. A., Duijf, P. H. G., Doetsch, V., Irvine, A. D., de Waal, R., Vanmolkot, K. R. J., Wessagowit, V., Kelly, A., Atherton, D. J., Griffiths, W. A. D., Orlow, S. J., van Haeringen, A., Ausems, M. G. E. M., Yang, A., McKeon, F., Bamshad, M. A., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63.</strong> Hum. Molec. Genet. 10: 221-229, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159940</a>] [<a href="https://doi.org/10.1093/hmg/10.3.221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159940">McGrath et al. (2001)</a> identified a T-to-G transversion at nucleotide 1564 of the TP63 gene, resulting in a cys526-to-gly substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a>, this mutation is designated cys522 to gly. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11159940+9774969" 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://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006911" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006911" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006911</a>
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<p>In a 10.5-year-old patient with features of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (<a href="/entry/103285">103285</a>), <a href="#2" class="mim-tip-reference" title="Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T. <strong>TP63 gene mutation in ADULT syndrome.</strong> Europ. J. Hum. Genet. 9: 642-645, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528512</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200676" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528512">Amiel et al. (2001)</a> described a heterozygous A-to-C transversion at position 16 in exon 3-prime of the TP63 gene, resulting in an asn6-to-his (N6H) substitution between the transactivation and DNA binding domains. The mutation affected exon 3-prime present only in the isotypes lacking the transactivation domain of the protein. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome, and was absent from a panel of 250 control chromosomes. <a href="#2" class="mim-tip-reference" title="Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T. <strong>TP63 gene mutation in ADULT syndrome.</strong> Europ. J. Hum. Genet. 9: 642-645, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528512</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200676" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528512">Amiel et al. (2001)</a> considered incomplete penetrance as the most likely explanation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528512" 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">rs2108864814 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108864814;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=rs2108864814" 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=rs2108864814" 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=RCV000006912" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006912" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006912</a>
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<p>In a patient (BX) with limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), who had bilateral split hand/foot malformation, isolated cleft palate, and normal hair, skin, and teeth, but absent nipples, <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al. (2001)</a> identified heterozygosity for a de novo 2-bp deletion (1576_1577delTT) in exon 13 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein within the SAM domain. The numbering of the mutation is according to the sequence reported by <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a>. The mutation was not found in the proband's unaffected parents. <a href="#20" class="mim-tip-reference" title="Guazzarotti, L., Caprio, C., Rinne, T. K., Bosoni, M., Pattarino, G., Mauri, S., Tadini, G. L., van Bokhoven, H., Zuccotti, G. V. <strong>Limb-mammary syndrome (LMS) associated with internal female genitalia dysgenesia: a new genotype/phenotype correlation?</strong> Am. J. Med. Genet. 146A: 2001-2004, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18627043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18627043</a>] [<a href="https://doi.org/10.1002/ajmg.a.32371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18627043">Guazzarotti et al. (2008)</a> evaluated this patient at age 14 years for primary amenorrhea and found that, although she had normal development of external genitalia and pubic hair and normal morphology of the lower vaginal tract, she had absent uterus and ovaries; hormonal evaluation revealed hypergonadotropic hypogonadism with a very low plasma estrogen level. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11462173+18627043+9774969" 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">rs1721306735 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1721306735;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=rs1721306735" 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=rs1721306735" 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=RCV001324784 OR RCV002274186" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001324784, RCV002274186" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001324784...</a>
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<p>In a patient (DW) with limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), who had bilateral split hand/foot malformation, absent lacrimal punctae, submucous cleft palate, bilateral ear pits, somewhat dry skin on the trunk, absent nipples, and anteriorly placed anus, <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al. (2001)</a> identified heterozygosity for a de novo 2-bp deletion (1743delAA) in exon 14 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein. The numbering of the mutation is according to the sequence reported by <a href="#63" class="mim-tip-reference" title="Yang, A., Kaghad, M., Wang, Y., Gillett, E., Fleming, M. D., Dotsch, V., Andrews, N. C., Caput, D., McKeon, F. <strong>p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.</strong> Molec. Cell 2: 305-316, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80275-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774969">Yang et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11462173+9774969" 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">rs113993967 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993967;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=rs113993967" 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=rs113993967" 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=RCV000006914 OR RCV000794231 OR RCV001781195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006914, RCV000794231, RCV001781195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006914...</a>
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<p><a href="#17" class="mim-tip-reference" title="Duijf, P. H. G., Vanmolkot, K. R. J., Propping, P., Friedl, W., Krieger, E., McKeon, F., Dotsch, V., Brunner, H. G., van Bokhoven, H. <strong>Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63.</strong> Hum. Molec. Genet. 11: 799-804, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929852</a>] [<a href="https://doi.org/10.1093/hmg/11.7.799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11929852">Duijf et al. (2002)</a> reported a 2-generation family with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (<a href="/entry/103285">103285</a>) whose affected individuals were heterozygous for an arg298-to-gln (R298Q) mutation. The mutation is located in the DNA binding domain of p63; however, unlike mutations in EEC syndrome, the R298Q mutation does not impair DNA binding. Rather, the mutation confers novel transcription activation capacity on the delta-N-p63-gamma isoform, which normally does not possess such activity. The authors concluded that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Rinne, T., Spadoni, E., Kjaer, K. W., Danesino, C., Larizza, D., Kock, M., Huoponen, K., Savontaus, M.-L., Aaltonen, M., Duijf, P., Brunner, H. G., Penttinen, M., van Bokhoven, H. <strong>Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.</strong> Europ. J. Hum. Genet. 14: 904-910, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16724007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16724007</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16724007">Rinne et al. (2006)</a> reported 2 unrelated families with ADULT syndrome in which affected members carried the R298Q mutation. The authors identified another mutation in the same codon, R298G (<a href="#0022">603273.0022</a>), in a third family with ADULT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16724007" 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 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular cardiomyopathy, <a href="#56" class="mim-tip-reference" title="Valenzise, M., Arrigo, T., De Luca, F., Privitera, A., Frigiola, A., Carando, A., Garelli, E., Silengo, M. <strong>R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy. (Letter)</strong> Europ. J. Med. Genet. 51: 497-500, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18603493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18603493</a>] [<a href="https://doi.org/10.1016/j.ejmg.2008.05.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18603493">Valenzise et al. (2008)</a> identified the R298Q mutation in the TP63 gene. The patient presented with asthenia and dyspnea and was found to have ectodermal signs including hypodontia, lacrimal duct aplasia, dystrophic nails, sparse, fragile, and wiry hair, decreased sweating, and absent right nipple. He had normal hands and feet with no radiographic anomalies. Cardiologic findings were consistent with the diagnosis of arrhythmogenic right ventricular cardiomyopathy by morphologic, functional, electrocardiographic, and histologic features. A cardioverter defibrillator was implanted 1 year after diagnosis. His mother, who had absent nipples and hypodontia but no cardiac defects or arrhythmia, also carried the R298Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18603493" 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>.0015 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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TP63, ASP312GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908844;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=rs121908844" 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=rs121908844" 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=RCV000006915 OR RCV000326964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006915, RCV000326964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006915...</a>
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<p>In a Japanese girl with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>) who developed diffuse large B-cell type non-Hodgkin lymphoma, <a href="#1" class="mim-tip-reference" title="Akahoshi, K., Sakazume, S., Kosaki, K., Ohashi, H., Fukushima, Y. <strong>EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.</strong> Am. J. Med. Genet. 120A: 370-373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838557</a>] [<a href="https://doi.org/10.1002/ajmg.a.20064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12838557">Akahoshi et al. (2003)</a> identified heterozygosity for a 1079A-G transition in exon 8 of the TP63 gene, resulting in a germline asp312-to-gly (D312G) mutation. They speculated that p63 may exert a biologic function as a tumor suppressor and suggested that malignant lymphoma should be considered an important complication of EEC3, inasmuch as 2 previous reports had also documented an association of EEC syndrome with malignant lymphoma (<a href="#19" class="mim-tip-reference" title="Gershoni-Baruch, R., Goldscher, D., Hochberg, Z. <strong>Ectrodactyly-ectodermal dysplasia-clefting syndrome and hypothalamo-pituitary insufficiency.</strong> Am. J. Med. Genet. 68: 168-172, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9028452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9028452</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19970120)68:2<168::aid-ajmg9>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9028452">Gershoni-Baruch et al., 1997</a>; <a href="#36" class="mim-tip-reference" title="Ogutcen-Toller, M., Gulen, O., Okten, G., Elbistan, M. <strong>Non-Hodgkin's lymphoma in a patient with ectrodactyly ectodermal dysplasia-clefting syndrome. (Letter)</strong> Oral Surg. Oral Med. Oral Path. Oral Radiol. Endod. 90: 124-125, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10936828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10936828</a>] [<a href="https://doi.org/10.1067/moe.2000.107171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10936828">Ogutcen-Toller et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10936828+12838557+9028452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<strong>.0016 RAPP-HODGKIN SYNDROME</strong>
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TP63, 1-BP DEL, 1709A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108873431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108873431;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=rs2108873431" 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=rs2108873431" 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=RCV000006916" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006916" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006916</a>
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<p>In a 32-year-old male with features consistent with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#10" class="mim-tip-reference" title="Bougeard, G., Hadj-Rabia, S., Faivre, L., Sarafan-Vasseur, N., Frebourg, T. <strong>The Rapp-Hodgkin syndrome results from mutations of the TP63 gene.</strong> Europ. J. Hum. Genet. 11: 700-704, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939657</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939657">Bougeard et al. (2003)</a> identified heterozygosity for a 1-bp deletion (1709delA) in exon 14 of the TP63 gene, resulting in a stop codon 22 amino acids downstream of the normal stop codon. This mutation is located in the post-SAM region and is predicted to affect only the TP63-alpha isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939657" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0017 RAPP-HODGKIN SYNDROME</strong>
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TP63, 1-BP DEL, 1859A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108874645 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108874645;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=rs2108874645" 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=rs2108874645" 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=RCV000006917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006917</a>
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<p>In 2 sibs and their mother who had been diagnosed with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#16" class="mim-tip-reference" title="Dianzani, I., Garelli, E., Gustavsson, P., Carando, A., Gustafsson, B., Dahl, N., Anneren, G. <strong>Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene.</strong> J. Med. Genet. 40: e133, 2003. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684701</a>] [<a href="https://doi.org/10.1136/jmg.40.12.e133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684701">Dianzani et al. (2003)</a> identified a 1-bp deletion (1859delA) in exon 14 of the TP63 gene, causing a frameshift at codon 620 affecting the alpha tail. The mutation was not found in an unaffected sib. The mother's clinical history revealed that she had a slight ankyloblepharon on the right eye at birth which was surgically treated; <a href="#16" class="mim-tip-reference" title="Dianzani, I., Garelli, E., Gustavsson, P., Carando, A., Gustafsson, B., Dahl, N., Anneren, G. <strong>Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene.</strong> J. Med. Genet. 40: e133, 2003. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684701</a>] [<a href="https://doi.org/10.1136/jmg.40.12.e133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14684701">Dianzani et al. (2003)</a> suggested that ankyloblepharon-ectodermal defects-clefting syndrome (AEC; <a href="/entry/106260">106260</a>) and RHS are the same clinical entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684701" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<strong>.0018 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE</strong>
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RAPP-HODGKIN SYNDROME, INCLUDED
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TP63, ILE510THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908845;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=rs121908845" 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=rs121908845" 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=RCV000006918 OR RCV000006919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006918, RCV000006919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006918...</a>
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<p>In a patient with ankyloblepharon-ectodermal defects-clefting syndrome (AEC; <a href="/entry/106260">106260</a>) previously described by <a href="#8" class="mim-tip-reference" title="Bertola, D. R., Kim, C. A., Sugayama, S. M. M., Albano, L. M. J., Utagawa, C. Y., Gonzalez, C. H. <strong>AEC syndrome and CHAND syndrome: further evidence of clinical overlapping in the ectodermal dysplasias.</strong> Pediat. Derm. 17: 218-221, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10886756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10886756</a>] [<a href="https://doi.org/10.1046/j.1525-1470.2000.01756.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10886756">Bertola et al. (2000)</a> and in a patient with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#7" class="mim-tip-reference" title="Bertola, D. R., Kim, C. A., Albano, L. M. J., Scheffer, H., Meijer, R., van Bokhoven, H. <strong>Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. (Letter)</strong> Clin. Genet. 66: 79-80, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200513</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00278.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15200513">Bertola et al. (2004)</a> identified a 1529C-to-T transition in exon 12 of the TP63 gene, predicting an ile510-to-thr (I510T) substitution. Both cases were sporadic. <a href="#7" class="mim-tip-reference" title="Bertola, D. R., Kim, C. A., Albano, L. M. J., Scheffer, H., Meijer, R., van Bokhoven, H. <strong>Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. (Letter)</strong> Clin. Genet. 66: 79-80, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200513</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00278.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15200513">Bertola et al. (2004)</a> concluded that AEC and RHS represent variable expression of a single genetic disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15200513+10886756" 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>.0019 RAPP-HODGKIN SYNDROME</strong>
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TP63, ARG545PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908846 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908846;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908846?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908846" 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=rs121908846" 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=RCV000006920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006920</a>
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<p>In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#25" class="mim-tip-reference" title="Kantaputra, P. N., Hamada, T., Kumchai, T., McGrath, J. A. <strong>Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia.</strong> J. Dent. Res. 82: 433-437, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12766194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12766194</a>] [<a href="https://doi.org/10.1177/154405910308200606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12766194">Kantaputra et al. (2003)</a> identified heterozygosity for a 1633T-C transition in exon 13 of the TP63 gene, resulting in a ser545-to-pro (S545P) substitution in the fourth helix of the sterile alpha motif (SAM) domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12766194" 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://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006921" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006921" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006921</a>
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<p>In a patient with ADULT syndrome (<a href="/entry/103285">103285</a>), <a href="#47" class="mim-tip-reference" title="Slavotinek, A. M., Tanaka, J., Winder, A., Vargervik, K., Haggstrom, A., Bamshad, M. <strong>Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome: report of a child with phenotypic overlap with ulnar-mammary syndrome and a new mutation in TP63.</strong> Am. J. Med. Genet. 138A: 146-149, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16114047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16114047</a>] [<a href="https://doi.org/10.1002/ajmg.a.30900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16114047">Slavotinek et al. (2005)</a> identified a heterozygous 518G-A transition in exon 4 of the TP63 gene, resulting in a val114-to-met (V114M) substitution. The patient had fifth finger brachydactyly and camptodactyly, ulnar ray hypoplasia, and imperforate anus, suggesting phenotypic overlap with ulnar-mammary syndrome (<a href="/entry/181450">181450</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16114047" 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">rs121908847 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908847;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=rs121908847" 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=rs121908847" 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=RCV000006922 OR RCV002467435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006922, RCV002467435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006922...</a>
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<p>In a 4-year-old Thai girl with orofacial cleft (OFC8; <a href="/entry/618149">618149</a>), <a href="#28" class="mim-tip-reference" title="Leoyklang, P., Siriwan, P., Shotelersuk, V. <strong>A mutation of the p63 gene in non-syndromic cleft lip. (Letter)</strong> J. Med. Genet. 43: e28, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740912[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.036442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16740912">Leoyklang et al. (2006)</a> found a heterozygous 937A-G transition in exon 8 of the TP63 gene, resulting in an arg313-to-gly (R313G) substitution at a highly conserved residue in the DNA binding domain. The patient had a surgically repaired bilateral complete cleft lip. The mutation was not found in her unaffected parents or in 1,000 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16740912" 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>.0022 ADULT 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">rs113993966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113993966;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=rs113993966" 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=rs113993966" 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=RCV000006923 OR RCV001280741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006923, RCV001280741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006923...</a>
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<p>In affected members of a Finnish family with ADULT syndrome (<a href="/entry/103285">103285</a>), <a href="#43" class="mim-tip-reference" title="Rinne, T., Spadoni, E., Kjaer, K. W., Danesino, C., Larizza, D., Kock, M., Huoponen, K., Savontaus, M.-L., Aaltonen, M., Duijf, P., Brunner, H. G., Penttinen, M., van Bokhoven, H. <strong>Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.</strong> Europ. J. Hum. Genet. 14: 904-910, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16724007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16724007</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16724007">Rinne et al. (2006)</a> identified a heterozygous 892C-G transversion in the TP63 gene, resulting in an arg298-to-gly (R298G) substitution. This substitution occurs in the same codon as another variant reported in ADULT syndrome (R298Q; <a href="#0014">603273.0014</a>). In vitro functional expression studies showed that the R298G mutation resulted in increased transcription activation, similar to the R298Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16724007" 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>.0023 SPLIT-HAND/FOOT MALFORMATION 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908848;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908848?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908848" 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=rs121908848" 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=RCV000006924 OR RCV001851711 OR RCV005031401" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006924, RCV001851711, RCV005031401" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006924...</a>
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<p>In a Mexican child with isolated unilateral split-hand malformation (SHFM4; <a href="/entry/605289">605289</a>), <a href="#67" class="mim-tip-reference" title="Zenteno, J. C., Berdon-Zapata, V., Kofman-Alfaro, S., Mutchinick, O. M. <strong>Isolated ectrodactyly caused by a heterozygous missense mutation in the transactivation domain of TP63.</strong> Am. J. Med. Genet. 134A: 74-76, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15736220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15736220</a>] [<a href="https://doi.org/10.1002/ajmg.a.30277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15736220">Zenteno et al. (2005)</a> identified a heterozygous 289C-T transition in exon 3 of the TP63 gene, resulting in an arg97-to-cys (R97C) substitution in the transactivation domain. The child also had a small scalp lesion, or aplasia cutis, which may or may not have been related to the TP63 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15736220" 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>.0024 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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ADULT SYNDROME, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908849 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908849;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=rs121908849" 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=rs121908849" 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=RCV000006925 OR RCV000006926 OR RCV000413620 OR RCV001390108" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006925, RCV000006926, RCV000413620, RCV001390108" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006925...</a>
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<p>In affected individuals from 3 unrelated families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), 2 of which were previously reported by <a href="#35" class="mim-tip-reference" title="O'Quinn, J. R., Hennekam, R. C. M., Jorde, L. B., Bamshad, M. <strong>Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19.</strong> Am. J. Hum. Genet. 62: 130-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9443880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9443880</a>] [<a href="https://doi.org/10.1086/301687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9443880">O'Quinn et al. (1998)</a>, <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al. (2001)</a> identified heterozygosity for a 797G-A transition in the TP63 gene, resulting in an arg227-to-gln (R227Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9443880+11462173" 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="#49" class="mim-tip-reference" title="Sripathomsawat, W., Tanpaiboon, P., Heering, J., Dotsch, V., Hennekam, R. C. M., Kantaputra, P. <strong>Phenotypic analysis of Arg227 mutations of TP63 with emphasis on dental phenotype and micturition difficulties in EEC syndrome. (Letter)</strong> Am. J. Med. Genet. 155A: 228-232, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21204238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21204238</a>] [<a href="https://doi.org/10.1002/ajmg.a.33768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21204238">Sripathomsawat et al. (2011)</a> provided follow-up of a remotely consanguineous Dutch family with EEC3, previously reported by <a href="#30" class="mim-tip-reference" title="Maas, S. M., de Jong, T. P. V. M., Buss, P., Hennekam, R. C. M. <strong>EEC syndrome and genitourinary anomalies: an update.</strong> Am. J. Med. Genet. 63: 472-478, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8737655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8737655</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960614)63:3<472::AID-AJMG11>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8737655">Maas et al. (1996)</a> and <a href="#35" class="mim-tip-reference" title="O'Quinn, J. R., Hennekam, R. C. M., Jorde, L. B., Bamshad, M. <strong>Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19.</strong> Am. J. Hum. Genet. 62: 130-135, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9443880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9443880</a>] [<a href="https://doi.org/10.1086/301687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9443880">O'Quinn et al. (1998)</a>, in which affected members were heterozygous for the R227Q mutation. Twelve newly affected individuals were identified, with marked phenotypic variability. Limb defects were present in 12 of 26 affected members, including 6 with split hand/foot and 1 with mesoaxial polydactyly. Two had cleft lip/palate, and 3 had mild manifestations of this features, such as indentation of the upper vermilion border. One individual had features of the AEC syndrome (<a href="/entry/106260">106260</a>). Features of ectodermal dysplasia were also variable. Most had blonde, sparse hair with slow growth, thin nails, periorbital hyperpigmentation, and dental caries. Four had hypodontia, and 8 were edentulous on examination. Most notable, 12 of those affected had micturition difficulties, which tended to improve with age, and 1 had defecation difficulties. <a href="#49" class="mim-tip-reference" title="Sripathomsawat, W., Tanpaiboon, P., Heering, J., Dotsch, V., Hennekam, R. C. M., Kantaputra, P. <strong>Phenotypic analysis of Arg227 mutations of TP63 with emphasis on dental phenotype and micturition difficulties in EEC syndrome. (Letter)</strong> Am. J. Med. Genet. 155A: 228-232, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21204238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21204238</a>] [<a href="https://doi.org/10.1002/ajmg.a.33768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21204238">Sripathomsawat et al. (2011)</a> emphasized that patients with EEC3 should have systematic dental examinations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9443880+21204238+8737655" 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 mother and daughter with ADULT syndrome (<a href="/entry/103285">103285</a>), <a href="#39" class="mim-tip-reference" title="Reisler, T. T., Patton, M. A., Meagher, P. P. J. <strong>Further phenotypic and genetic variation in ADULT syndrome.</strong> Am. J. Med. Genet. 140A: 2495-2500, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17041931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17041931</a>] [<a href="https://doi.org/10.1002/ajmg.a.31482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17041931">Reisler et al. (2006)</a> identified the R227Q mutation in exon 6 of the TP63 gene and suggested that there may be considerable overlap between the EEC and ADULT syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17041931" 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 affected members of 2 unrelated families with EEC syndrome, features of limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), and severe micturition difficulties, <a href="#31" class="mim-tip-reference" title="Maclean, K., Holme, S. A., Gilmour, E., Taylor, M., Scheffer, H., Graf, N., Smith, G. H. H., Onikul, E., van Bokhoven, H., Moss, C., Ades, L. C. <strong>EEC syndrome, arg227-to-gln TP63 mutation and micturition difficulties: is there a genotype-phenotype correlation?</strong> Am. J. Med. Genet. 143A: 1114-1119, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17431922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17431922</a>] [<a href="https://doi.org/10.1002/ajmg.a.31664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17431922">Maclean et al. (2007)</a> identified the R227Q mutation in the TP63 gene. Noting that 4 of the 6 cases/families reported with this mutation had manifested similar urinary symptoms (see <a href="#58" class="mim-tip-reference" title="van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others. <strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong> Am. J. Hum. Genet. 69: 481-492, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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/10.1086/323123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11462173">van Bokhoven et al., 2001</a>), the authors suggested that this represents a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11462173+17431922" 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 mother and daughter with Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>) associated with corneal dystrophy and premature menopause, <a href="#22" class="mim-tip-reference" title="Holder-Espinasse, M., Martin-Coignard, D., Escande, F., Manouvrier-Hanu, S. <strong>A new mutation in TP63 is associated with age-related pathology.</strong> Europ. J. Hum. Genet. 15: 1115-1120, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17609671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17609671</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17609671">Holder-Espinasse et al. (2007)</a> identified heterozygosity for a 1-bp deletion (1783delC) in the TP63 gene, resulting in a frameshift and a protein that is 22 amino acids longer than wildtype. The authors stated that this was the first report of these associated age-related features in RHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17609671" 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 Dutch mother and daughter with minimal manifestations of ADULT syndrome (<a href="/entry/103285">103285</a>), <a href="#59" class="mim-tip-reference" title="van Zelst-Stams, W. A. G., van Steensel, M. A. M. <strong>A novel TP63 mutation in a family with ADULT syndrome presenting with eczema and hypothelia. (Letter)</strong> Am. J. Med. Genet. 149A: 1558-1560, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19530185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19530185</a>] [<a href="https://doi.org/10.1002/ajmg.a.32881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19530185">van Zelst-Stams and van Steensel (2009)</a> identified heterozygosity for a 380C-T transition in the TP63 gene, resulting in a pro127-to-leu (P127L) substitution at a highly conserved residue in the C-terminal end of the proline-rich domain. The mutation was not found in 100 unrelated Dutch controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19530185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 11-year-old boy who displayed an overlapping phenotype with features of both ankyloblepharon-ectodermal defects-clefting syndrome (AEC; <a href="/entry/106260">106260</a>) and Rapp-Hodgkin syndrome (RHS; <a href="/entry/129400">129400</a>), <a href="#38" class="mim-tip-reference" title="Prontera, P., Escande, F., Cocchi, G., Donti, E., Martini, A., Sensi, A. <strong>An intermediate phenotype between Hays-Wells and Rapp-Hodgkin syndromes in a patient with a novel p63 mutation: confirmation of a variable phenotypic spectrum with a common aetiology.</strong> Genet. Counsel. 19: 397-402, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19239083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19239083</a>]" pmid="19239083">Prontera et al. (2008)</a> identified heterozygosity for an 11-bp duplication (1716dupCTCCCCTTCTC) in exon 14 of the TP63 gene, predicted to result in a protein that is 26 amino acids longer than wildtype. The mutation is located in the transcriptional inhibitory domain (TID) and is predicted to affect only the TP63-alpha isoforms. The patient was born with bilateral ankyloblepharon filiforme adnatum and submucous cleft palate and was diagnosed with AEC syndrome; however, he had only slight erythema of the scalp without infection or erosion or areas of eczematous skin. Upon reevaluation at age 11 years, he showed facial dysmorphism including high frontal hairline, hypoplastic alae nasi, pinched and narrow nose, midface hypoplasia with relative prognathism, and had hypohidrosis and syndactyly, features more suggestive of a diagnosis of RHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19239083" 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>.0028 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908849 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908849;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=rs121908849" 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=rs121908849" 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=RCV000023290 OR RCV004719659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023290, RCV004719659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023290...</a>
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<p>In a Thai father and his daughter with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; <a href="/entry/604292">604292</a>), <a href="#49" class="mim-tip-reference" title="Sripathomsawat, W., Tanpaiboon, P., Heering, J., Dotsch, V., Hennekam, R. C. M., Kantaputra, P. <strong>Phenotypic analysis of Arg227 mutations of TP63 with emphasis on dental phenotype and micturition difficulties in EEC syndrome. (Letter)</strong> Am. J. Med. Genet. 155A: 228-232, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21204238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21204238</a>] [<a href="https://doi.org/10.1002/ajmg.a.33768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21204238">Sripathomsawat et al. (2011)</a> identified a heterozygous 680G-C transversion in exon 6 of the TP63 gene, resulting in an arg227-to-pro (R227P) substitution in a highly conserved residue. The mutation was not found in 100 Thai control individuals. The 4-year-old daughter had dry and sparse dark hair, left cleft lip and palate, depressed nasal bridge, slightly dry skin, and thin nails. She had split hands and split right foot, as well as syndactyly of the right fourth and fifth toes. Her father had normal dark hair, dry skin, split right hand, bifid right thumb, and flexion contracture of the distal phalanx of the left index finger. His second toes were small and slender, and he had underdeveloped toenails. The father had significant dental involvement, with enamel hypoplasia, extensive dental caries, hypodontia of the mandibular canines, generalized microdontia, prominent marginal ridges of permanent maxillary incisors, round-shaped permanent molars, and barrel-shaped permanent maxillary central incisors. Although the mutation affected the same residue as a mutation found in a Dutch family with EEC3 and significant micturition difficulties (R227Q; <a href="#0024">603273.0024</a>), neither of the Thai patients had micturition problems. <a href="#49" class="mim-tip-reference" title="Sripathomsawat, W., Tanpaiboon, P., Heering, J., Dotsch, V., Hennekam, R. C. M., Kantaputra, P. <strong>Phenotypic analysis of Arg227 mutations of TP63 with emphasis on dental phenotype and micturition difficulties in EEC syndrome. (Letter)</strong> Am. J. Med. Genet. 155A: 228-232, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21204238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21204238</a>] [<a href="https://doi.org/10.1002/ajmg.a.33768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21204238">Sripathomsawat et al. (2011)</a> emphasized that patients with EEC3 should have systematic dental examinations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21204238" 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">rs1560277554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560277554;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=rs1560277554" 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=rs1560277554" 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=RCV000710017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000710017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000710017</a>
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<p>In a family (CLP-1055) in which the proband and his father had orofacial cleft (OFC8; <a href="/entry/618149">618149</a>), <a href="#4" class="mim-tip-reference" title="Basha, M., Demeer, B., Revencu, N., Helaers, R., Theys, S., Saba, S. B., Boute, O., Devauchelle, B., Francois, G., Bayet, B., Vikkula, M. <strong>Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes.</strong> J. Med. Genet. 55: 449-458, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29500247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29500247</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-105110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29500247">Basha et al. (2018)</a> identified heterozygosity for a 2-bp duplication (c.819-820dupCC, NM_003722.4) in exon 6 of the TP63 gene, resulting in a frameshift and a premature termination codon (Gln274fsTer4) in the evolutionarily conserved DNA binding domain. mRNA studies demonstrated nonsense-mediated mRNA decay of the mutant allele. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. The son had a unilateral right-sided cleft lip and his father had a unilateral left-sided cleft lip. Neither patient had any symptoms of other TP63 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29500247" 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>.0030 PREMATURE OVARIAN FAILURE 21</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs900140738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs900140738;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs900140738?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs900140738" 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=rs900140738" 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=RCV000766166 OR RCV003159542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000766166, RCV003159542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000766166...</a>
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<p>In a 16-year-old girl (patient 8) with primary amenorrhea (POF21; <a href="/entry/620311">620311</a>), <a href="#55" class="mim-tip-reference" title="Tucker, E. J., Jaillard, S., Grover, S. R., van den Bergen, J., Robevska, G., Bell, K. M., Sadedin, S., Hanna, C., Dulon, J., Touraine, P., Sinclair, A. H. <strong>TP63-truncating variants cause isolated premature ovarian insufficiency.</strong> Hum. Mutat. 40: 886-892, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30924587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30924587</a>] [<a href="https://doi.org/10.1002/humu.23744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30924587">Tucker et al. (2019)</a> identified heterozygosity for a de novo c.1780C-T transition (c.1780C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg594-to-ter (R594X) substitution within the sterile alpha motif, truncating TP63 before the transactivation inhibitory domain. The mutation was not found in her unaffected parents or in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30924587" 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 27-year-old Chinese woman (patient 5) with primary amenorrhea and nonvisualization of the ovaries on ultrasound, <a href="#23" class="mim-tip-reference" title="Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S. <strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong> J. Clin. Invest. 133: e162315, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36856110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36856110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36856110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI162315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36856110">Huang et al. (2023)</a> identified heterozygosity for the R594X mutation in the TP63 gene. The authors noted that the R594X variant was present at low minor allele frequency in the gnomAD and ExAC databases (MAFs, 0.00003290 and 0.00007419, respectively). Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the R594X mutant. BN-PAGE analysis suggested that the R594X mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R594X mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36856110" 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>.0031 PREMATURE OVARIAN FAILURE 21</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">rs1560311010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560311010;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=rs1560311010" 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=rs1560311010" 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=RCV000766167 OR RCV003159543" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000766167, RCV003159543" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000766167...</a>
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<p>In a woman (FRA125) with primary amenorrhea (POF21; <a href="/entry/620311">620311</a>), <a href="#55" class="mim-tip-reference" title="Tucker, E. J., Jaillard, S., Grover, S. R., van den Bergen, J., Robevska, G., Bell, K. M., Sadedin, S., Hanna, C., Dulon, J., Touraine, P., Sinclair, A. H. <strong>TP63-truncating variants cause isolated premature ovarian insufficiency.</strong> Hum. Mutat. 40: 886-892, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30924587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30924587</a>] [<a href="https://doi.org/10.1002/humu.23744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30924587">Tucker et al. (2019)</a> identified heterozygosity for a c.1794G-A transition (c.1794G-A, NM_003722.4) in exon 14 of the TP63 gene, resulting in a trp598-to-ter (W598X) substitution. Parental DNA status was not reported, but the mutation was not found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30924587" 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>.0032 PREMATURE OVARIAN FAILURE 21</strong>
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TP63, ARG97PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002291803 OR RCV003159546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002291803, RCV003159546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002291803...</a>
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<p>In a 24-year-old woman and her paternal aunt with secondary amenorrhea and atrophic ovaries (POF21; <a href="/entry/620311">620311</a>), <a href="#54" class="mim-tip-reference" title="Tucker, E. J., Gutfreund, N., Belaud-Rotureau, M. A., Gilot, D., Brun, T., Kline, B. L., Bell, K. M., Domin-Bernhard, M., Theard, C., Touraine, P., Robevska, G., van van den Bergen, J., Ayers, K. L., Sinclair, A. H., Dotsch, V., Jaillard, S. <strong>Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.</strong> Hum. Mutat. 43: 1443-1453, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35801529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35801529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35801529[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/10.1002/humu.24432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35801529">Tucker et al. (2022)</a> identified heterozygosity for a c.290G-C transversion (c.290G-C, NM_003722.5) in exon 3 of the TP63 gene, resulting in an arg97-to-pro (R97P) substitution at a highly conserved residue within the N-terminal TAD of the TAp63-alpha isoform. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R97P substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35801529" 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>.0033 PREMATURE OVARIAN FAILURE 21</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002291804 OR RCV003159547" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002291804, RCV003159547" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002291804...</a>
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<p>In a 27-year-old woman with secondary amenorrhea and atrophic ovaries devoid of follicles (POF21; <a href="/entry/620311">620311</a>), <a href="#54" class="mim-tip-reference" title="Tucker, E. J., Gutfreund, N., Belaud-Rotureau, M. A., Gilot, D., Brun, T., Kline, B. L., Bell, K. M., Domin-Bernhard, M., Theard, C., Touraine, P., Robevska, G., van van den Bergen, J., Ayers, K. L., Sinclair, A. H., Dotsch, V., Jaillard, S. <strong>Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.</strong> Hum. Mutat. 43: 1443-1453, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35801529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35801529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35801529[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/10.1002/humu.24432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35801529">Tucker et al. (2022)</a> identified heterozygosity for a paternally inherited c.1939C-T transition (c.1939C-T, NM_003722.5) in exon 14 of the TP63 gene, resulting in an arg647-to-cys (R647C) substitution at a highly conserved residue within the C-terminal TID. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R647C substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35801529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated Chinese women (patients 8, 9, and 10) with secondary amenorrhea and nonvisualization of the ovaries on ultrasound, <a href="#23" class="mim-tip-reference" title="Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S. <strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong> J. Clin. Invest. 133: e162315, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36856110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36856110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36856110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI162315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36856110">Huang et al. (2023)</a> identified heterozygosity for the R647C mutation in the TP63 gene. The R647C variant was not found in the ExAC database, but was present at low minor allele frequency in gnomAD (MAF, 0.00001316). Western blot of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but significantly reduced expression of the R647C mutant. BN-PAGE analysis suggested that the R647C mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R647C mutant. Mice heterozygous for the R647C mutation showed accelerated oocyte loss, reduced fertility, and impaired oocyte quality, but the phenotypes were less severe than mice carrying a mutation that truncated the TID. The authors noted that this was consistent with patients carrying the R647C mutation presenting with secondary amenorrhea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36856110" 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>.0034 PREMATURE OVARIAN FAILURE 21</strong>
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TP63, 1-BP DEL, 1703A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003159548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003159548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003159548</a>
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<p>In a 32-year-old Chinese woman (patient 4) with primary amenorrhea (POF21; <a href="/entry/620311">620311</a>), <a href="#23" class="mim-tip-reference" title="Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S. <strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong> J. Clin. Invest. 133: e162315, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36856110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36856110</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36856110[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI162315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36856110">Huang et al. (2023)</a> identified heterozygosity for a 1-bp deletion (c.1703delA, NM_003722.5) in exon 13 of the TP63 gene, causing a frameshift predicted to result in a premature termination codon (Gln568fsTer3). The mutation was not found in the ExAC or gnomAD databases. Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the Gln568fsTer3 mutant. BN-PAGE analysis suggested that the Gln568fsTer3 mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the Gln568fsTer3 mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36856110" 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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TP63, ARG643TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1560311554 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1560311554;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=rs1560311554" 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=rs1560311554" 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=RCV000760773 OR RCV003159544" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000760773, RCV003159544" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000760773...</a>
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<p>In 6 affected individuals over 2 generations of a Danish family with an atypical form of limb-mammary syndrome (LMS; <a href="/entry/603543">603543</a>), <a href="#32" class="mim-tip-reference" title="Mathorne, S. W., Ravn, P., Hansen, D., Beck-Nielsen, S. S., Gjorup, H., Sorensen, K. P., Fagerberg, C. R. <strong>Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect.</strong> Clin. Genet. 97: 779-784, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32067224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32067224</a>] [<a href="https://doi.org/10.1111/cge.13725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32067224">Mathorne et al. (2020)</a> identified heterozygosity for a c.1927C-T transition (c.1927C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg643-to-ter (R643X) substitution within the transactivation inhibitory domain (TID). The mutation segregated with disease in the family and was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32067224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Akahoshi2003" class="mim-anchor"></a>
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Akahoshi, K., Sakazume, S., Kosaki, K., Ohashi, H., Fukushima, Y.
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<strong>EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.</strong>
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Am. J. Med. Genet. 120A: 370-373, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838557</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20064" target="_blank">Full Text</a>]
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Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T.
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<strong>TP63 gene mutation in ADULT syndrome.</strong>
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Europ. J. Hum. Genet. 9: 642-645, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528512</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200676" target="_blank">Full Text</a>]
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Augustin, M., Bamberger, C., Paul, D., Schmale, H.
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<strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong>
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Mammalian Genome 9: 899-902, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799841</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9799841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s003359900891" target="_blank">Full Text</a>]
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Basha, M., Demeer, B., Revencu, N., Helaers, R., Theys, S., Saba, S. B., Boute, O., Devauchelle, B., Francois, G., Bayet, B., Vikkula, M.
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<strong>Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes.</strong>
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J. Med. Genet. 55: 449-458, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29500247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29500247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29500247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Beaudry, V. G., Pathak, N., Koster, M. I., Attardi, L. D.
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<strong>Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.</strong>
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Am. J. Med. Genet. 149A: 1952-1957, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19353588[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=19353588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32760" target="_blank">Full Text</a>]
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Benard, J., Douc-Rasy, S., Ahomadegbe, J.-C.
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<strong>TP53 family members and human cancers.</strong>
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Hum. Mutat. 21: 182-191, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12619104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12619104</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12619104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10172" target="_blank">Full Text</a>]
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Bertola, D. R., Kim, C. A., Albano, L. M. J., Scheffer, H., Meijer, R., van Bokhoven, H.
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<strong>Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. (Letter)</strong>
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Clin. Genet. 66: 79-80, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200513</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15200513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.0009-9163.2004.00278.x" target="_blank">Full Text</a>]
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Bertola, D. R., Kim, C. A., Sugayama, S. M. M., Albano, L. M. J., Utagawa, C. Y., Gonzalez, C. H.
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<strong>AEC syndrome and CHAND syndrome: further evidence of clinical overlapping in the ectodermal dysplasias.</strong>
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Pediat. Derm. 17: 218-221, 2000.
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[<a href="https://doi.org/10.1046/j.1525-1470.2000.01756.x" target="_blank">Full Text</a>]
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<strong>The p63 target HBP1 is required for skin differentiation and stratification.</strong>
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[<a href="https://doi.org/10.1038/cdd.2010.59" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.10778" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81646-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/onc.2012.497" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2011.01.013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0503437102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.40.12.e133" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.7.799" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19970120)68:2<168::aid-ajmg9>3.0.co;2-l" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32371" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201888" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI162315" target="_blank">Full Text</a>]
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Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P.
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<strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong>
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[<a href="https://doi.org/10.1086/302972" target="_blank">Full Text</a>]
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</p>
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<strong>Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia.</strong>
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[<a href="https://doi.org/10.1177/154405910308200606" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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<strong>p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors.</strong>
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[<a href="https://doi.org/10.1073/pnas.0602477103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32415" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.036442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/dev.011759" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960614)63:3<472::AID-AJMG11>3.0.CO;2-J" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31664" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.13725" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32793" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Valenzise, M., Arrigo, T., De Luca, F., Privitera, A., Frigiola, A., Carando, A., Garelli, E., Silengo, M.
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<strong>R298Q mutation of p63 gene in autosomal dominant ectodermal dysplasia associated with arrhythmogenic right ventricular cardiomyopathy. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18603493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18603493</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18603493" 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.ejmg.2008.05.005" target="_blank">Full Text</a>]
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</p>
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<a id="57" class="mim-anchor"></a>
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<a id="van Bokhoven2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Bokhoven, H., Brunner, H. G.
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<strong>Splitting p63.</strong>
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Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12037717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12037717</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12037717[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=12037717" 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/10.1086/341450" target="_blank">Full Text</a>]
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</p>
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<a id="58" class="mim-anchor"></a>
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<a id="van Bokhoven2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H. G., Vanmolkot, K. R. J., van Beusekom, E., van Beersum, S. E. C., Celli, J., Merkx, G. F. M., Tenconi, R., and 13 others.
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<strong>p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation.</strong>
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Am. J. Hum. Genet. 69: 481-492, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11462173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11462173</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11462173[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=11462173" 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/10.1086/323123" target="_blank">Full Text</a>]
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</p>
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<a id="59" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>A novel TP63 mutation in a family with ADULT syndrome presenting with eczema and hypothelia. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19530185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19530185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19530185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32881" target="_blank">Full Text</a>]
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</p>
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<a id="Vaughan2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vaughan, A. E., Brumwell, A. N., Xi, Y., Gotts, J. E., Brownfield, D. G., Treutlein, B., Tan, K., Tan, V., Liu, F. C., Looney, M. R., Matthay, M. A., Rock, J. R., Chapman, H. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25533958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25533958</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25533958[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=25533958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature14112" target="_blank">Full Text</a>]
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<div class="">
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Venkatanarayan, A., Raulji, P., Norton, W., Chakravarti, D., Coarfa, C., Su, X., Sandur, S. K., Ramirez, M. S., Lee, J., Kingsley, C. V., Sananikone, E. F., Rajapakshe, K., Naff, K., Parker-Thornburg, J., Bankson, J. A., Tsai, K. Y., Gunaratne, P. H., Flores, E. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25409149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25409149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25409149[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=25409149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13910" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774969</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774969" 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/s1097-2765(00)80275-0" target="_blank">Full Text</a>]
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</p>
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<a id="Yang1999" class="mim-anchor"></a>
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<p class="mim-text-font">
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Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N., Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C., McKeon, F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10227294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10227294</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10227294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/19539" target="_blank">Full Text</a>]
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</p>
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<a id="65" class="mim-anchor"></a>
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<a id="Yi2008" class="mim-anchor"></a>
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<strong>A skin microRNA promotes differentiation by repressing 'stemness.'</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18311128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18311128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18311128[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=18311128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature06642" target="_blank">Full Text</a>]
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<a id="Zarnegar2012" class="mim-anchor"></a>
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22922031[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=22922031" 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.2012.07.007" target="_blank">Full Text</a>]
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<a id="67" class="mim-anchor"></a>
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<a id="Zenteno2005" class="mim-anchor"></a>
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Zenteno, J. C., Berdon-Zapata, V., Kofman-Alfaro, S., Mutchinick, O. M.
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<strong>Isolated ectrodactyly caused by a heterozygous missense mutation in the transactivation domain of TP63.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15736220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15736220</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15736220" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30277" target="_blank">Full Text</a>]
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<a id="Zuo2015" class="mim-anchor"></a>
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Zuo, W., Zhang, T., Wu, D. Z., Guan, S. P., Liew, A.-A., Yamamoto, Y., Wang, X., Lim, S. J., Vincent, M., Lessard, M., Crum, C. P., Xian, W., McKeon, F.
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<strong>p63+Krt5+ distal airway stem cells are essential for lung regeneration.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25383540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25383540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25383540[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=25383540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13903" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Bao Lige - updated : 10/05/2023
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Marla J. F. O'Neill - updated : 04/04/2023<br>Marla J. F. O'Neill - updated : 04/04/2023<br>Bao Lige - updated : 04/30/2020<br>Carol A. Bocchini - updated : 10/14/2018<br>Ada Hamosh - updated : 2/2/2016<br>Ada Hamosh - updated : 2/2/2016<br>Paul J. Converse - updated : 12/23/2015<br>Patricia A. Hartz - updated : 11/17/2014<br>Patricia A. Hartz - updated : 12/19/2013<br>Patricia A. Hartz - updated : 10/3/2012<br>Patricia A. Hartz - updated : 4/26/2012<br>Cassandra L. Kniffin - updated : 1/5/2012<br>Marla J. F. O'Neill - updated : 7/12/2011<br>Patricia A. Hartz - updated : 5/5/2011<br>Ada Hamosh - updated : 12/27/2010<br>Marla J. F. O'Neill - updated : 6/9/2010<br>Marla J. F. O'Neill - updated : 1/22/2010<br>Marla J. F. O'Neill - updated : 12/4/2009<br>Marla J. F. O'Neill - updated : 8/17/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 7/18/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>Ada Hamosh - updated : 5/21/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Marla J. F. O'Neill - updated : 4/13/2007<br>Marla J. F. O'Neill - updated : 2/5/2007<br>Ada Hamosh - updated : 2/1/2007<br>Cassandra L. Kniffin - updated : 10/2/2006<br>Cassandra L. Kniffin - updated : 9/21/2006<br>Patricia A. Hartz - updated : 8/15/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Cassandra L. Kniffin - updated : 10/21/2005<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Patricia A. Hartz - updated : 8/15/2005<br>Marla J. F. O'Neill - updated : 5/5/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 1/22/2004<br>Victor A. McKusick - updated : 8/5/2003<br>George E. Tiller - updated : 10/29/2002<br>Victor A. McKusick - updated : 10/16/2002<br>Victor A. McKusick - updated : 7/17/2002<br>Ada Hamosh - updated : 4/9/2002<br>Michael B. Petersen - updated : 11/29/2001<br>George E. Tiller - updated : 4/18/2001<br>Victor A. McKusick - updated : 9/8/2000<br>Ada Hamosh - updated : 8/14/2000<br>Victor A. McKusick - updated : 7/25/2000<br>Stylianos E. Antonarakis - updated : 11/11/1999<br>Victor A. McKusick - updated : 4/8/1999
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 11/10/1998
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</span>
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</div>
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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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 01/15/2025
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/15/2024<br>mgross : 10/05/2023<br>carol : 05/10/2023<br>carol : 04/05/2023<br>alopez : 04/04/2023<br>carol : 04/04/2023<br>mgross : 04/30/2020<br>carol : 10/14/2018<br>carol : 01/05/2018<br>carol : 04/12/2016<br>alopez : 2/29/2016<br>alopez : 2/2/2016<br>alopez : 2/2/2016<br>mgross : 12/23/2015<br>carol : 6/4/2015<br>mgross : 11/19/2014<br>mcolton : 11/17/2014<br>mgross : 1/9/2014<br>mcolton : 12/19/2013<br>carol : 9/26/2013<br>carol : 7/26/2013<br>alopez : 3/14/2013<br>terry : 11/29/2012<br>terry : 11/29/2012<br>mgross : 10/4/2012<br>terry : 10/3/2012<br>mgross : 4/26/2012<br>carol : 1/11/2012<br>ckniffin : 1/5/2012<br>carol : 11/22/2011<br>alopez : 9/2/2011<br>wwang : 7/15/2011<br>terry : 7/12/2011<br>mgross : 6/8/2011<br>terry : 5/5/2011<br>alopez : 1/5/2011<br>alopez : 1/5/2011<br>terry : 12/27/2010<br>terry : 12/8/2010<br>wwang : 6/10/2010<br>terry : 6/9/2010<br>terry : 4/2/2010<br>wwang : 1/28/2010<br>terry : 1/22/2010<br>carol : 12/23/2009<br>terry : 12/4/2009<br>carol : 8/17/2009<br>wwang : 6/15/2009<br>terry : 6/1/2009<br>wwang : 5/7/2009<br>ckniffin : 4/16/2009<br>mgross : 9/19/2008<br>wwang : 7/18/2008<br>terry : 7/18/2008<br>mgross : 5/29/2008<br>terry : 5/28/2008<br>alopez : 5/27/2008<br>terry : 5/21/2008<br>wwang : 2/7/2008<br>terry : 2/1/2008<br>wwang : 4/20/2007<br>terry : 4/13/2007<br>wwang : 2/5/2007<br>alopez : 2/5/2007<br>terry : 2/1/2007<br>carol : 1/25/2007<br>wwang : 10/6/2006<br>ckniffin : 10/2/2006<br>wwang : 9/25/2006<br>ckniffin : 9/21/2006<br>mgross : 8/15/2006<br>carol : 7/11/2006<br>carol : 7/11/2006<br>terry : 6/27/2006<br>alopez : 5/10/2006<br>wwang : 11/8/2005<br>ckniffin : 10/21/2005<br>wwang : 10/7/2005<br>terry : 9/29/2005<br>mgross : 8/15/2005<br>wwang : 8/5/2005<br>terry : 8/4/2005<br>carol : 8/3/2005<br>carol : 6/2/2005<br>terry : 5/27/2005<br>wwang : 5/9/2005<br>wwang : 5/5/2005<br>alopez : 3/2/2005<br>tkritzer : 1/22/2004<br>tkritzer : 10/6/2003<br>tkritzer : 8/7/2003<br>tkritzer : 8/5/2003<br>tkritzer : 8/5/2003<br>carol : 7/10/2003<br>carol : 1/30/2003<br>terry : 1/6/2003<br>tkritzer : 12/10/2002<br>cwells : 10/29/2002<br>carol : 10/25/2002<br>tkritzer : 10/23/2002<br>terry : 10/16/2002<br>tkritzer : 7/26/2002<br>terry : 7/17/2002<br>alopez : 4/11/2002<br>terry : 4/9/2002<br>mgross : 2/21/2002<br>cwells : 12/14/2001<br>cwells : 12/5/2001<br>cwells : 11/29/2001<br>alopez : 5/11/2001<br>cwells : 4/26/2001<br>cwells : 4/18/2001<br>terry : 3/20/2001<br>mcapotos : 9/26/2000<br>carol : 9/26/2000<br>mcapotos : 9/19/2000<br>terry : 9/8/2000<br>alopez : 8/18/2000<br>terry : 8/14/2000<br>alopez : 7/25/2000<br>mgross : 11/16/1999<br>mgross : 11/11/1999<br>carol : 4/8/1999<br>carol : 11/10/1998
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603273
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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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TUMOR PROTEIN p63; TP63
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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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<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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TUMOR PROTEIN p73-LIKE; TP73L<br />
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p53-RELATED PROTEIN p63; p63<br />
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KET
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</span>
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</h4>
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</div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TP63</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> 55821006, 720464003, 721972001, 7731005;
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</span>
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</p>
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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-text-font">
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<strong>
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<em>
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Cytogenetic location: 3q28
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:189,596,746-189,897,276 </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="8">
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<span class="mim-font">
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3q28
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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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ADULT 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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103285
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 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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604292
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Hay-Wells 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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106260
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Limb-mammary 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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603543
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Orofacial cleft 8
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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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618149
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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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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Premature ovarian failure 21
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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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620311
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Rapp-Hodgkin 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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129400
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Split-hand/foot malformation 4
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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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605289
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Yang et al. (1998) described the cloning of tumor protein p63, which shows strong homology to the tumor suppressor p53 (191170) and the p53-related protein p73 (601990). p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. The p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. The predominant p63 isoforms in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. The full-length p63 protein contains 448 amino acids. Isoforms of p63 are due to alternative promoters in exons 1 or 3 and alternative splicing of exons at the 3-prime end. These truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63. Yang et al. (1998) suggested the possibility of physiologic interactions among members of the p53 family. </p><p>Augustin et al. (1998) also cloned a cDNA, which they termed KET, that is related to the tumor suppressor p53. They stated that the 4,846-bp KET cDNA encodes a protein of 680 amino acids that shares 98% identity with the rat homolog. The remarkable degree of conservation lent support to the notion that KET proteins have important basic functions in development and differentiation. </p><p>Di Iorio et al. (2005) stated that the p63 gene generates 6 isoforms. The transactivating isoforms are generated by the activity of an upstream promoter, and the N-terminally truncated (delta-N) isoforms, which lack the transactivation domain, are produced from a downstream intronic promoter. For both transcripts, alternative splicing gives rise to 3 different C termini, designated alpha, beta, and gamma. </p><p>Deutsch et al. (2011) stated that full-length TAp63-alpha contains an N-terminal transactivation domain, followed by a DNA-binding domain, an oligomerization domain, a sterile-alpha motif (SAM) domain, and a C-terminal transactivation inhibitory (TI) domain. </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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<strong>Gene Structure</strong>
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<p>Yang et al. (1998) determined that the TP63 gene contains 15 exons. </p>
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<strong>Mapping</strong>
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<p>By fluorescence in situ hybridization, Yang et al. (1998) localized the human TP63 gene to chromosome 3q27-q29. Using linkage analysis, they mapped the mouse gene to chromosome 16 in a region known to be syntenic with human 3q27-q29. </p><p>By radiation hybrid analysis, Augustin et al. (1998) mapped the TP63 gene to human chromosome 3q27. KET (TP63) is located between the somatostatin gene (SST; 182450) proximally and the apolipoprotein D gene (APOD; 107740) distally. By means of an interspecific backcross panel, Augustin et al. (1998) mapped the murine homolog, Ket, to chromosome 16 in a region that is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the Loh2 gene, a putative suppressor of angiogenesis. Augustin et al. (1998) inferred from mapping data that KET may act as a tumor suppressor and should be considered a candidate for Loh2. </p>
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<strong>Gene Function</strong>
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<p>Hibi et al. (2000) stated that p53 (191170) homologs known variously as p40, p51, p63, and p73L (Trink et al., 1998, Yang et al., 1998, Osada et al., 1998, Senoo et al., 1998) are isoforms of the same gene, which Hibi et al. (2000) referred to as AIS for 'amplified in squamous cell carcinoma.' The main difference between the various transcripts is the presence or absence of the N-terminal transcriptional activation domain; p40, delta-Np63, and p73L lack this domain. Though no evidence of a tumor suppressor function was found, Hibi et al. (2000) observed overexpression of this gene in head and neck cancer cell lines and primary lung cancers associated with a low increase of its copy number. Amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68(AIS) lacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Results were interpreted as indicating that AIS transcripts lacking the N-terminal transcriptional activation domain play an oncogenic rather than a suppressive role in certain cancers. </p><p>Flores et al. (2002) explored the role of p63 and p73 in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for 1 or a combination of these p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene. While using the E1A system facilitated the performance of biochemical analyses, the authors also examined the functions of p63 and p73 using an in vivo system in which apoptosis had been shown to be dependent on p53. Using both systems, Flores et al. (2002) demonstrated that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage. Note that an Expression of Concern was published for the article by Flores et al. (2002). </p><p>Benard et al. (2003) suggested that the 2 homologs of TP53, TP73 and TP63, must not have a typical tumor suppressor gene role in human cancers, given the lack of demonstrated mutations in either of these 2 genes. Nevertheless, TP73 and TP63 seem strongly involved in malignancy acquisition and maintenance. </p><p>Using DNA microarray analysis with transfected human SAOS2 osteosarcoma cells, Wu et al. (2003) found that both delta-Np63-alpha and TAp63-alpha could activate gene transcription. A comparison of gene profiles revealed that these p63 isoforms influenced a wide variety of partly overlapping targets involved in cell cycle control, stress, and signal transduction. Delta-Np63-alpha and TAp63-alpha often influenced expression of specific genes in an opposite manner. </p><p>Di Iorio et al. (2005) found that, depending on the conditions, limbal and corneal keratinocytes may contain all 3 delta-N isoforms of p63. In the uninjured surface of the eye, delta-N p63-alpha was present in the limbus but was absent from the corneal epithelium. Delta-N p63-beta and delta-N p63-gamma appeared upon wounding, and their expression correlated with limbal cell migration and corneal regeneration and differentiation. Di Iorio et al. (2005) concluded that the alpha isoform is necessary for maintenance of the proliferative potential of limbal stem cells and their ability to migrate over the cornea. The beta and gamma isoforms, being suprabasal and virtually absent from the resting limbus, likely play a role in epithelial differentiation during corneal regeneration. </p><p>Suh et al. (2006) showed that p63, and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. They also showed that DNA damage induced both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. Suh et al. (2006) concluded that their data supported a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germline, whereas the functions of p53 are restricted to vertebrate somatic cells for tumor suppression. </p><p>Yi et al. (2008) showed that miR203 (611899) is induced in the skin concomitantly with stratification and differentiation. By altering miR203's spatiotemporal expression in vivo, they showed that miR203 promotes epidermal differentiation by restricting proliferative potential and inducing cell cycle exit. Yi et al. (2008) identified p63 as one of the conserved targets of miR203 across vertebrates. Notably, p63 is an essential regulator of stem cell maintenance in stratified epithelial tissues. Yi et al. (2008) showed that miR203 directly represses the expression of p63; it fails to switch off suprabasally when either Dicer1 (606241) or miR203 is absent and it becomes repressed basally when miR203 is prematurely expressed. The authors concluded that miR203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighboring layers. </p><p>Su et al. (2010) showed that TAp63 suppresses tumorigenesis and metastasis, and coordinately regulates Dicer (606241) and miR130b (613682) to suppress metastasis. Metastatic mouse and human tumors deficient in TAp63 express Dicer at very low levels, and Su et al. (2010) found that modulation of expression of Dicer and miR130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. Su et al. (2010) concluded that their data provided a novel understanding of the roles of TAp63 in tumor and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR130b, and may have implications for the many processes regulated by miRNAs. </p><p>Using RNA interference screening to identify targets of p63 in human keratinocytes, Borrelli et al. (2010) showed that HBP1 (616714) was directly repressed by p63. Mice lacking p63 showed increased Hbp1 expression in keratinocytes. HBP1 was activated upon human keratinocyte differentiation and was required for keratinocyte stratification. Borrelli et al. (2010) concluded that suppression of HBP1 enables p63-mediated growth promotion in the lower layers of epidermis and that HBP1 coordinates expression of genes involved in stratification, leading to formation of the skin barrier. </p><p>Deutsch et al. (2011) found that TAp63-alpha was maintained in a closed dimeric and inactive conformation in nonstressed murine oocytes. Phosphorylation opened the dimer and permitted formation of the active tetramer from 2 activated dimers. Dephosphorylation did not affect the oligomerization equilibrium. Mutation analysis showed that a helix within the oligomerization domain of TAp63-alpha was crucial for tetramer stabilization and essentially made the activation process irreversible. </p><p>By Western blot analysis of transfected 5637 human bladder cancer cells, Scheel et al. (2009) found that expression of a plasmid containing tandem sequences of all 4 MIR302 family members (see MIR302A; 614596) and MIR367 (614600) downregulated p63 expression. Mutation analysis identified 2 functional MIR302 binding sites in the 3-prime UTR of the p63 transcript. Western blot analysis showed that transfection of GH testicular cancer cells with antagonizing oligonucleotides that blocked all MIR302 subspecies resulted in elevated p63 protein levels. RT-PCR confirmed that synthetic MIR302B (614597) downregulated p63 mRNA expression. </p><p>Conforti et al. (2013) identified the human E3 ubiquitin ligase PIR2 (RNF144B; 618869) as a direct transcriptional target of p63 and found that PIR2 expression in keratinocytes and squamous cell carcinomas was predominantly dependent on p63. PIR2 depletion impaired proliferation of human epidermal keratinocytes. The authors found that PIR2 functioned downstream of p63 to regulate cell proliferation by mediating p21 (CDKN1A; 116899) degradation. PIR2 depletion also impaired keratinocyte differentiation, as PIR2 expression was required for termination of differentiation in keratinocytes. Moreover, PIR2 depletion increased p63 protein level in keratinocytes, as p63 regulated its own protein level by transcriptionally activating PIR2, leading to p63 proteasomal degradation. </p><p>Using mouse knockout models and transfected human cell lines, Restelli et al. (2014) found that DLX5 (600028) and TP63, which both can cause split hand/foot malformations when mutated, are involved in a regulatory loop during limb development. Proteasome-mediated degradation of delta-N p63-alpha was induced by the cis/trans isomerase PIN1 (601052). FGF8 (600483), a downstream DLX5 effector, countered delta-N p63-alpha degradation. Restelli et al. (2014) noted that both the Tp63 and Dlx5/Dlx6 (600030) mouse models of split hand/foot malformations show reduced Fgf8 expression in the apical ectodermal ridge. </p><p>In mice, Zuo et al. (2015) showed that preexisting, intrinsically committed distal airway stem cells expressing TRP63 and keratin-5 (KRT5; 148040), called DASC(p63/Krt5), undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. Zuo et al. (2015) also showed that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to prefibrotic lesions and deficient oxygen exchange. Finally, the authors demonstrated that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. Zuo et al. (2015) concluded that the ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases. </p><p>Vaughan et al. (2015) independently defined the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells that are present within normal distal lung. The authors stated that quiescent LNEPs activate a delta-Np63 (a p63 splice variant) and cytokeratin-5 (Krt5) remodeling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch (190198) signaling to activate the delta-Np63 and cytokeratin-5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signaling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signaling. Vaughan et al. (2015) concluded that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and that the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signaling. </p><p>The delta-N isoforms (lacking the acidic transactivation domain) of p63 and p73 (601990) are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53 (191170), p63 bearing the acidic transactivation domain (TAp63), and TAp73 to inhibit their tumor-suppressive functions. Venkatanarayan et al. (2015) showed that deletion of the delta-N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumors through upregulation of IAPP (147940), the gene that encodes amylin, a 37-amino-acid peptide cosecreted with insulin by the beta cells of the pancreas. Venkatanarayan et al. (2015) found that IAPP is causally involved in tumor regression and that amylin functions through the calcitonin receptor (CALCR; 114131) and RAMP3 (605155) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analog of amylin that is used to treat type 1 and type 2 diabetes, caused rapid tumor regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome 3</em></strong></p><p>
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Celli et al. (1999) mapped EEC3 (604292), an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts, to a region of 3q27 where an EEC-like disorder, limb-mammary syndrome (LMS; 603543), had been mapped. Analysis of the p63 gene, which is located in the critical LMS/EEC3 interval, revealed heterozygous mutations in 9 unrelated EEC3 families. (see, e.g., 603273.0001-603273.0004). Eight mutations resulted in amino acid substitutions that were predicted to abolish the DNA binding capacity of p63; the ninth was a frameshift mutation. Six of the 9 mutations were C-to-T transversions at CpG dinucleotides. Transactivation studies with these mutant p63 isotypes provided a molecular explanation for the dominant character of p63 mutations in EEC3. </p><p><strong><em>Split-Hand/Foot Malformation 4</em></strong></p><p>
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To assess the potential of p63 as a candidate gene for split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) analyzed the p63 gene in 2 multigenerational families with SHFM in which segregation analysis had excluded linkage to all previously identified autosomal regions. Two missense mutations, 724A-G in exon 5, which predicted a lys194-to-glu substitution (603273.0005), and 982T-C in exon 7, which predicted an arg280-to-cys substitution (603273.0006). Ianakiev et al. (2000) also identified mutations in the TP63 gene in families with EEC3; see 603273.0007 and 603273.0008. </p><p><strong><em>Ankyloblepharon-Ectodermal Defects-Clefting (AEC) Syndrome</em></strong></p><p>
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Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC; 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon, and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; 604292), limb-mammary syndrome (LMS; 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; 103285), and recessive cleft lip/palate-ectodermal dysplasia (CLPED1; 225060). McGrath et al. (2001) analyzed the p63 gene in AEC syndrome patients and identified missense mutations in 8 families (see, e.g., 603273.0009-603273.0010). </p><p>In a patient who displayed an overlapping phenotype with features of both AEC and Rapp-Hodgkin syndrome (RHS; 129400), Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027). </p><p>Rinne et al. (2009) analyzed the TP63 gene in 24 individuals from 12 different AEC families, and identified mutations in 21 of those tested; the 3 individuals without an identified mutation included 2 unaffected relatives and 1 patient with a phenotype slightly different than AEC/RHS. Of the 11 different mutations identified, 8 were within the coding region of the sterile alpha motif (SAM) domain, and 3 were located in the exon 14 sequence encoding the transactivation inhibitory (TI) domain. </p><p>Using luciferase reporter assays, Beaudry et al. (2009) demonstrated compromise of PERP (609301) induction with some (see 603273.0009) but not all AEC-patient derived TP63 mutants. Skin biopsy analysis of AEC patients revealed a subset displaying aberrant PERP expression, suggesting that PERP dysregulation might be involved in the pathogenesis of this disease. Beaudry et al. (2009) concluded that distinct AEC TP63 mutants could differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. </p><p>Using humanized mouse cDNAs expressed in regenerated human epidermal tissue and keratinocytes in culture, Zarnegar et al. (2012) found that AEC-related mutations within the SAM domain of Tp63 repressed expression of transcriptional activators and markers of epidermal differentiation compared with wildtype Tp63. AEC-mutant Tp63 did not induce apoptosis or alter keratinocyte proliferation. ZNF750 (610226), KLF4 (602253), and GRHL3 (608317) were among a group of epidermal genes significantly downregulated by AEC-related mutations. Chromatin immunoprecipitation analysis and sequencing showed that both wildtype and AEC-mutant Tp63 bound 2 canonical TP63-binding sites near the ZNF750 transcriptional start site. Expression of exogenous ZNF750 in AEC model tissue rescued expression of the majority of TP63 target genes. Introduction of Tp63 variants lacking the SAM domain did not alter expression of epidermal differentiation markers. </p><p>By determining the NMR structure of the p63 SAM domain with the AEC-associated mutation L514F, followed by funtional analyses with L514F and other AEC-associated mutations, Russo et al. (2018) showed that AEC mutations destabilized the SAM domain, leading to aggregation of the p63 protein. Moreover, AEC-associated p63 mutants not only caused aggregation of wildtype p63, but they also selectively bound other p53 family members and caused their aggregation. In vitro analysis and in vivo analysis of a mouse AEC model revealed that p63 aggregation impaired both the transactivation and repression functions of p63, as aggregated p63 mutant proteins had weakened ability to bind DNA. Reducing the aggregation propensity of AEC-associated mutant p63 proteins restored their transcriptional activity. </p><p><strong><em>ADULT Syndrome</em></strong></p><p>
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Amiel et al. (2001) reported a missense mutation (603273.0011) in the TP63 gene in an isolated case of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285), which maps to chromosome 3q27. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome. Amiel et al. (2001) considered incomplete penetrance as the most likely explanation. </p><p>In affected members of a 2-generation family with ADULT syndrome, Duijf et al. (2002) identified a heterozygous mutation in the TP63 gene (R298Q; 603273.0014). Rinne et al. (2006) identified the R298Q mutation in affected members of 2 unrelated families with ADULT syndrome; 1 was Italian, and the other was Dutch. A third family of Finnish origin had a different mutation at the same codon (R298G; 603273.0022). </p><p>In a Dutch mother and daughter with minimal manifestations of ADULT syndrome, including hypothelia and palmar hyperlinearity, van Zelst-Stams and van Steensel (2009) identified heterozygosity for a missense mutation in the C-terminal end of the proline-rich domain of TP63 (P127L; 603273.0026). The authors stated that mutations in this domain have primarily been reported to cause limb-mammary syndrome. </p><p>In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular dysplasia, who did not have the skin and limb manifestations of ADULT syndrome, Valenzise et al. (2008) identified the R298Q mutation in the TP63 gene. The mutation was also found in his mother, who displayed only hypodontia and athelia. Valenzise et al. (2008) noted that their findings highlighted the clinical overlapping of TP63-related ectodermal dysplasias and the difficulty of establishing unequivocal genotype-phenotype correlations. </p><p><strong><em>Limb-Mammary Syndrome</em></strong></p><p>
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In 2 unrelated patients with limb-mammary syndrome (LMS; 603543), van Bokhoven et al. (2001) sequenced the TP63 gene and identified heterozygosity for 2 different frameshift mutations: a 2-bp deletion in exon 13 (603273.0012) and a 2-bp deletion in exon 14 (603273.0013). </p><p>In affected members of a Danish family with features of LMS but without limb anomalies, Mathorne et al. (2020) identified heterozygosity for a nonsense mutation in the TP63 gene (R643X; 603273.0035). </p><p><strong><em>Rapp-Hodgkin Syndrome</em></strong></p><p>
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In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; 129400), Kantaputra et al. (2003) identified heterozygosity for a missense mutation (S545P; 603273.0019) in the TP73L gene. Kantaputra et al. (2003) stated that this was the first genetic abnormality to be described in RHS, and noted that this provides molecular data to support the clinically observed overlap between EEC, AEC, and RHS. </p><p>In a mother and daughter with RHS associated with corneal dystrophy and premature menopause, Holder-Espinasse et al. (2007) identified heterozygosity for a 1-bp deletion in the TP73L gene (603273.0025). </p><p>In a patient who displayed an overlapping phenotype with features of both AEC and RHS, Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027). </p><p><strong><em>Orofacial Cleft 8</em></strong></p><p>
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Because mutations in the TP63 gene underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate, Leoyklang et al. (2006) performed mutation analysis of the 16 exons of the gene in 100 Thai patients with nonsyndromic CL/P (OFC8; 618149). In total, 21 single nucleotide changes were found, of which 6 were in the coding regions, including 3 novel nonsynonymous changes: S90L, R313G (603273.0021), and D564H. The R313G change was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, occurrence in a functionally important domain, predicted damaging function, de novo occurrence, and its absence in 500 control individuals. The finding highlighted further the wide phenotypic spectrum of TP63 gene mutations. </p><p>In a family (CLP-1055) in which the proband and his father had orofacial cleft-8, Basha et al. (2018) identified heterozygosity for a 2-bp duplication (603273.0029) in the TP63 gene. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. Neither patient had any symptoms of other TP63 disorders. </p><p><strong><em>Premature Ovarian Failure 21</em></strong></p><p>
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In 2 unrelated women with isolated primary amenorrhea (POF21; 620311) who were negative for mutation in known POF-associated genes, Tucker et al. (2019) identified heterozygosity for 2 different nonsense mutations in the last exon (exon 14) of the TP63 gene, R594X (603273.0030) and W598X (603273.0031). In the family for which parental DNA was available, the mutation was shown to have arisen de novo; neither mutation was found in public variant databases. </p><p>In 3 unrelated women with premature ovarian failure, Tucker et al. (2022) identified heterozygosity for missense mutations in the TP63 gene, including R97P (603273.0032) and R647C (603273.0033), which were shown to disrupt TP63 dimerization, causing an open active tetramer conformation with a significant increase in transcriptional activity. The third variant, Y18C, had no detectable impact on conformation or transcriptional activity. Tucker et al. (2022) suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes. </p><p>Huang et al. (2023) analyzed WES data from a cohort of 1,030 Chinese women diagnosed with premature ovarian insufficiency, and identified 8 unrelated Chinese women with heterozygous mutations in the TP63 gene, including 3 with secondary amenorrhea and the previously reported R647C mutation, and 1 with primary amenorrhea and the R594X mutation. All but 1 of the mutations were in exon 14; patient 4, who had primary amenorrhea, was heterozygous for a 1-bp deletion in exon 13 (603273.0034). The mutations were confirmed by Sanger sequencing and were either not found or were present at low minor allele frequency in the ExAC and/or gnomAD databases. Functional analysis suggested that variants affecting the C-terminal transactivation-inhibitory domain disrupt the inactive TP63 conformation, generating constitutively active TAp63-alpha that increases expression of target genes and induces apoptosis, thus causing exhaustion of oocytes that results in premature ovarian failure. </p><p><strong><em>Functional Effects of p63 Mutations</em></strong></p><p>
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Using mouse models, Lo Iacono et al. (2008) found that p63 mutations associated with split-hand/foot malformation (e.g., K194E; 603273.0005) and ectrodactyly-ectodermal dysplasia-cleft lip (e.g., R279H; 603273.0007), which lie within the DNA-binding domain of p63, reduced the ability of p63 to activate DLX5 (600028) and DLX6 (600030) promoter reporter constructs. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the TP63 gene and lung cancer, see 614210.</p><p>For discussion of a possible association between homozygosity or heterozygosity for a rare TP63 insertion polymorphism (rs34201045) and SHFM caused by mutation in the WNT10B gene (601906), see SHFM6 (225300).</p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Ianakiev et al. (2000) identified 4 TP63 mutations in patients with SHFM4 and EEC3. All 4 mutations were found in exons that fall within the DNA-binding domain of p63. The 2 amino acids mutated in the families with SHFM appeared to be involved primarily in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with DNA. </p><p>McGrath et al. (2001) noted that p63 mutations resulting in the AEC syndrome result in amino acid substitutions in the sterile alpha motif (SAM) domain and are predicted to affect protein-protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. The authors suggested that a distinct genotype-phenotype correlation can be recognized for EEC and AEC syndromes. </p><p>Van Bokhoven and Brunner (2002) reviewed the spectrum of p63 mutations underlying 5 human malformation syndromes. Clustering of mutations established a clear genotype-phenotype correlation: in the DNA binding domain (DBD) for EEC syndrome and in the SAM domain for AEC syndrome. Limb-mammary syndrome (LMS; 603543) differs from EEC syndrome in at least 3 respects: (1) mammary gland and nipple hypoplasia are consistent features of LMS but are only occasionally seen in EEC syndrome; (2) patients with LMS do not have the hair and skin defects that are seen in EEC syndrome; (3) whereas patients with LMS have cleft palate, those with EEC syndrome have cleft lip/palate but never have cleft palate only. Phenotypically, LMS is most similar to ADULT syndrome. Two isolated patients with an LMS phenotype had, in exons 13 and 14, frameshift mutations that resulted in truncation of the p63-alpha protein. Therefore, the abundant p63 product in epithelial cells would be missing the transactivation inhibitory domain (TID). </p><p>Brunner et al. (2002) reviewed p63 mutations causing developmental syndromes. They stated that the pattern of heterozygous mutations is distinct for each syndrome, and that consistent with this syndrome-specific mutation pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function. </p><p>Rinne et al. (2006) reviewed the clinical features of 227 patients with p63 mutations and detailed the variable phenotypic features associated with 5 mutation hotspots, which are all C-T transitions at CpG islands (see 603273.0001; 603273.0006-603273.0008; 603273.0024). </p><p>In affected members of 2 unrelated families with EEC syndrome, features of LMS, and severe micturition difficulties, Maclean et al. (2007) identified the R227Q mutation in the TP73L gene (603273.0024). The authors stated that 4 of the 6 cases/families reported with EEC and the R227Q mutation have manifested this distinct urologic abnormality (see van Bokhoven et al., 2001), indicative of a genotype/phenotype correlation. </p>
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<strong>Animal Model</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Yang et al. (1999) generated mice deficient in p63 by targeted disruption. p63 -/- mice have major defects in their limb, craniofacial, and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches, and epidermal appendages, which are all sites of reciprocal signaling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge (AER), which is essential for limb development. The embryonic epidermis of p63 -/- mice undergoes an unusual process of nonregenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrimal, and salivary glands. Yang et al. (1999) concluded that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis. </p><p>Mills et al. (1999) independently generated mice deficient in p63. The p63-deficient mice were born alive but had striking developmental defects. Their limbs were absent or truncated, defects that were caused by a failure of the AER to differentiate. The skin of p63-deficient mice did not progress past an early developmental stage: it lacked stratification and did not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth, and mammary glands, were absent in p63-deficient mice. </p><p>Keyes et al. (2006) studied spontaneous tumorigenesis in p63 +/- mice in both wildtype and p53-compromised backgrounds. p63 +/- mice were not tumor prone, and mice heterozygous for both p63 and p53 had fewer tumors than p53 +/- mice. The rare tumors that developed in mice with compromised p63 were distinct from those of p53 +/- mice. Furthermore, p63 +/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. Keyes et al. (2006) concluded that p63 plays a markedly different role in tumor formation than p53. </p><p>Suzuki et al. (2008) showed that Dlx5 (600028), Dlx6 (600030), p63, and Bmp7 (112267), a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice. </p><p>The AER is a transitory multilayered ectoderm acting as a signaling center essential for distal limb development and digit patterning. Lo Iacono et al. (2008) stated that the normal stratified organization of the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6 double-knockout limbs. They found that p63 colocalized with Dlx5 and Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5 and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63 isoform expressed in developing limbs. Delta-N p63-alpha bound and activated transcription of Dlx5 and Dlx6 reporter constructs. Other delta-N isoforms were less active, and isoforms containing the N-terminal transactivation domain showed no activity with Dlx5 and Dlx6 reporters. </p><p>Su et al. (2010) generated mice lacking TAp63. In 2.5 years of study, both heterozygous and TAp63-null mice developed spontaneous carcinomas and sarcomas and had a significantly shorter life span than the wildtype cohort. Paradoxically, a larger proportion of TAp63-null mice (24%) were tumor-free compared with TAp63 heterozygous mice (15%). Su et al. (2010) concluded that their data suggested that TAp63 is a haploinsufficient tumor suppressor gene. Consistent with this finding, sarcomas and carcinomas from TAp63 heterozygous mice retained the wildtype allele of TAp63. TAp63 heterozygous and null mice developed highly metastatic tumors and 10% of these metastases were found in the brain, a rare finding in spontaneous mouse tumor models. </p><p>Huang et al. (2023) generated mice with a stop codon prior to the TID in exon 14 of the p63 gene, selectively altering the oocyte-specific p63-alpha isoform. Heterozygous mutant females were infertile, whereas mutant males were fertile. Ovary size in the mutant female mice was markedly reduced, and the number of follicles was substantially reduced at postnatal day 1 (P1), with follicles completely absent by P21. Oocyte numbers were reduced to approximately 40% of those of wildtype mice, and had completely disappeared by P10. The mutant females showed elevated FSH and decreased estradiol levels. The authors suggested that expression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype. Immunofluorescence staining of P1 ovarian sections showed a significant increase in cleaved-PARP1 (173870)-positive oocytes in mutant ovaries compared to wildtype. Increased expression of Bax (600040), Puma (BBC3; 605854), and Noxa (PMAIP1; 604959) was observed, suggesting that deleting the TID of the p63 protein was sufficient to induce uncontrolled apoptosis of oocytes in primordial follicles without exogenous damage. In vitro analysis in SAOS-2 cells confirmed that activated p63 lacking the TID triggers downstream proapoptotic pathways, causing oocyte exhaustion and infertility. </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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<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>35 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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TP63, ARG204TRP
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<br />
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SNP: rs121908835,
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ClinVar: RCV000006900, RCV000394306, RCV000812084, RCV002283440, RCV005025017
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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 3 unrelated patients with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-trp (R204W) mutation in the DNA binding domain of TP63. The mutation segregated with the disease in 2 families and was not found in normal controls. In the third family, the mutation occurred de novo. </p><p>Kosaki et al. (2008) reported a Japanese male infant with EEC3 who was found to be heterozygous for the R204W mutation. He had a classic phenotype with split hand-foot malformation and cleft lip and palate. His father, who was found to be somatic mosaic for the mutation, had split hand-foot malformation, no cleft lip or palate, and whorl-like streaky pigmentary patterns of the skin following Blaschko lines. He had gray hair on the right half of his scalp and brown thin hair on the left side. He also had enamel hypoplasia and partial anodontia. Extensive genetic analysis demonstrated that the father was mosaic for the mutation in peripheral blood and hair, although most of his sperm carried the mutation. Kosaki et al. (2008) concluded that the mutation was postzygotic in the father and resulted in gonosomal mosaicism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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TP63, ARG204GLN
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<br />
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SNP: rs121908836,
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ClinVar: RCV000006901, RCV000705452, RCV001804714, RCV002250454
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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 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-gln mutation in the core element II of the DNA binding domain of TP63. The mutation segregated with the disease and was not found in normal controls. </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 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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TP63, CYS306ARG
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<br />
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SNP: rs121908837,
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ClinVar: RCV000006902
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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 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous cys306-to-arg mutation in the core element IV of the DNA binding domain of TP63. The mutation was de novo and was not found in normal controls. Transactivation assays using cell lysates containing the cys306-to-arg mutation showed a total lack of transactivation activity. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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TP63, 1-BP INS, 1572A
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<br />
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SNP: rs2108864810,
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ClinVar: RCV000006903
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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 ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a 1-bp insertion (A) at nucleotide 1572 in exon 13 of the TP63 gene, resulting in a frameshift at codon 525 (tyr) and a premature stop codon in the same exon. The mutation was de novo. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SPLIT-HAND/FOOT MALFORMATION 4</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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TP63, LYS194GLU
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<br />
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SNP: rs121908838,
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ClinVar: RCV000006904
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with split-hand/foot malformation (SHFM4; 605289) from South Africa, previously reported by Spranger and Schapera (1988), Ianakiev et al. (2000) identified a 724A-G transition in exon 5 of the p63 gene, predicted to cause a lys194-to-glu (K194E) amino acid substitution. This family, designated R, was of mixed ancestry from Cape Province. The spectrum of clinical manifestations was broad, ranging from the presence of a split hand in 1 individual to bilateral monodactyly and unilateral aplasia of the right lower extremity with a split left foot in another individual. No family members had any significant abnormalities other than those of the extremities. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 SPLIT-HAND/FOOT MALFORMATION 4</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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TP63, ARG280CYS
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<br />
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SNP: rs121908839,
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ClinVar: RCV000006905, RCV001280776, RCV002512857, RCV003162215
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family of mixed ancestry from Cape Province, South Africa, with split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) identified a 982T-C transition in exon 7 of the TP63 gene, predicted to cause an arg280-to-cys (R280C) amino acid substitution. The phenotype in this family, designated A, ranged from severe 'lobster claw' malformations of the feet in 1 individual, to minor 3/4 syndactyly of the left foot appearing as the only manifestation in another individual. The daughter of the latter individual had distal duplications of her thumbs bilaterally with absence of the second and third phalanges of the right hand and an absent second phalanx with 3/4 syndactyly of the left hand. No members of the family had significant abnormality of the face, palate, skin, teeth, hair, or nails. No abnormalities of the mammary glands or nipples were noted. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
|
|
</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
RAPP-HODGKIN SYNDROME, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TP63, ARG279HIS
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<br />
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SNP: rs121908840,
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ClinVar: RCV000006906, RCV000006907, RCV000478736, RCV000548176
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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 />
|
|
<p><strong><em>Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome</em></strong></p><p>
|
|
In a study of 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Ianakiev et al. (2000) identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H) substitution, and a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution (603273.0008). </p><p><strong><em>Rapp-Hodgkin Syndrome</em></strong></p><p>
|
|
In a 25-year-old female with features consistent with Rapp-Hodgkin syndrome (RHS; 129400), Bougeard et al. (2003) identified heterozygosity for the R279H substitution. This residue corresponds to the R248 hotspot mutation in TP53 (see 191170), and occurs within the DNA-binding domain present within all of the TP63 isoforms. In vitro functional analysis showed that this mutation did not decrease the transcriptional activity of the TAp63-gamma isoform on a TP53 reporter system, but disrupted the dominant-negative activity of the delta-N-p63-alpha and -gamma isoforms on the transcriptional activity of TP53. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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TP63, ARG304GLN
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<br />
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SNP: rs121908841,
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ClinVar: RCV000006908, RCV000276670, RCV000655484, RCV001266717, RCV005025018
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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 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Ianakiev et al. (2000) identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution, and a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H; 603273.0007) substitution. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE</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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TP63, LEU514PHE
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<br />
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SNP: rs121908842,
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ClinVar: RCV000006909
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 6-year-old patient with Hay-Wells syndrome (AEC; 106260) who lacked any limb defects, McGrath et al. (2001) identified an A-to-T transversion at nucleotide 1542 of the TP63 gene, resulting in a leu518-to-phe substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by Yang et al. (1998), this mutation is designated leu514 to phe. </p><p>In a transactivation assay, Beaudry et al. (2009) demonstrated that TA-TP63-alpha-L514F was completely defective in activating the PERP (609301) luciferase reporter compared to wildtype. The authors hypothesized that specific protein-protein interactions needed for full PERP transactivation by TP63 are abolished when the structure of the sterile alpha motif (SAM) domain is compromised, as is the case with the L514F mutation. </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>.0010 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE</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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TP63, CYS522GLY
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<br />
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SNP: rs121908843,
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ClinVar: RCV000006910, RCV001067605
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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 10-month-old infant with typical features of Hay-Wells syndrome (AEC; 106260), McGrath et al. (2001) identified a T-to-G transversion at nucleotide 1564 of the TP63 gene, resulting in a cys526-to-gly substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by Yang et al. (1998), this mutation is designated cys522 to gly. </p>
|
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</span>
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</div>
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
|
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 ADULT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TP63, ASN6HIS
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|
<br />
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|
|
|
SNP: rs113993963,
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|
|
|
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|
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ClinVar: RCV000006911
|
|
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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 10.5-year-old patient with features of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285), Amiel et al. (2001) described a heterozygous A-to-C transversion at position 16 in exon 3-prime of the TP63 gene, resulting in an asn6-to-his (N6H) substitution between the transactivation and DNA binding domains. The mutation affected exon 3-prime present only in the isotypes lacking the transactivation domain of the protein. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome, and was absent from a panel of 250 control chromosomes. Amiel et al. (2001) considered incomplete penetrance as the most likely explanation. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
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|
</div>
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|
<div>
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|
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0012 LIMB-MAMMARY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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TP63, 2-BP DEL, 1576TT
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<br />
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SNP: rs2108864814,
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|
|
|
|
ClinVar: RCV000006912
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (BX) with limb-mammary syndrome (LMS; 603543), who had bilateral split hand/foot malformation, isolated cleft palate, and normal hair, skin, and teeth, but absent nipples, van Bokhoven et al. (2001) identified heterozygosity for a de novo 2-bp deletion (1576_1577delTT) in exon 13 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein within the SAM domain. The numbering of the mutation is according to the sequence reported by Yang et al. (1998). The mutation was not found in the proband's unaffected parents. Guazzarotti et al. (2008) evaluated this patient at age 14 years for primary amenorrhea and found that, although she had normal development of external genitalia and pubic hair and normal morphology of the lower vaginal tract, she had absent uterus and ovaries; hormonal evaluation revealed hypergonadotropic hypogonadism with a very low plasma estrogen level. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LIMB-MAMMARY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, 2-BP DEL, 1743AA
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|
<br />
|
|
|
|
SNP: rs1721306735,
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|
|
|
|
|
|
|
ClinVar: RCV001324784, RCV002274186
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (DW) with limb-mammary syndrome (LMS; 603543), who had bilateral split hand/foot malformation, absent lacrimal punctae, submucous cleft palate, bilateral ear pits, somewhat dry skin on the trunk, absent nipples, and anteriorly placed anus, van Bokhoven et al. (2001) identified heterozygosity for a de novo 2-bp deletion (1743delAA) in exon 14 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein. The numbering of the mutation is according to the sequence reported by Yang et al. (1998). </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ADULT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG298GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs113993967,
|
|
|
|
|
|
|
|
ClinVar: RCV000006914, RCV000794231, RCV001781195
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Duijf et al. (2002) reported a 2-generation family with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285) whose affected individuals were heterozygous for an arg298-to-gln (R298Q) mutation. The mutation is located in the DNA binding domain of p63; however, unlike mutations in EEC syndrome, the R298Q mutation does not impair DNA binding. Rather, the mutation confers novel transcription activation capacity on the delta-N-p63-gamma isoform, which normally does not possess such activity. The authors concluded that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63. </p><p>Rinne et al. (2006) reported 2 unrelated families with ADULT syndrome in which affected members carried the R298Q mutation. The authors identified another mutation in the same codon, R298G (603273.0022), in a third family with ADULT syndrome. </p><p>In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular cardiomyopathy, Valenzise et al. (2008) identified the R298Q mutation in the TP63 gene. The patient presented with asthenia and dyspnea and was found to have ectodermal signs including hypodontia, lacrimal duct aplasia, dystrophic nails, sparse, fragile, and wiry hair, decreased sweating, and absent right nipple. He had normal hands and feet with no radiographic anomalies. Cardiologic findings were consistent with the diagnosis of arrhythmogenic right ventricular cardiomyopathy by morphologic, functional, electrocardiographic, and histologic features. A cardioverter defibrillator was implanted 1 year after diagnosis. His mother, who had absent nipples and hypodontia but no cardiac defects or arrhythmia, also carried the R298Q mutation. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ASP312GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908844,
|
|
|
|
|
|
|
|
ClinVar: RCV000006915, RCV000326964
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese girl with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292) who developed diffuse large B-cell type non-Hodgkin lymphoma, Akahoshi et al. (2003) identified heterozygosity for a 1079A-G transition in exon 8 of the TP63 gene, resulting in a germline asp312-to-gly (D312G) mutation. They speculated that p63 may exert a biologic function as a tumor suppressor and suggested that malignant lymphoma should be considered an important complication of EEC3, inasmuch as 2 previous reports had also documented an association of EEC syndrome with malignant lymphoma (Gershoni-Baruch et al., 1997; Ogutcen-Toller et al., 2000). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 RAPP-HODGKIN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, 1-BP DEL, 1709A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2108873431,
|
|
|
|
|
|
|
|
ClinVar: RCV000006916
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old male with features consistent with Rapp-Hodgkin syndrome (RHS; 129400), Bougeard et al. (2003) identified heterozygosity for a 1-bp deletion (1709delA) in exon 14 of the TP63 gene, resulting in a stop codon 22 amino acids downstream of the normal stop codon. This mutation is located in the post-SAM region and is predicted to affect only the TP63-alpha isoforms. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 RAPP-HODGKIN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, 1-BP DEL, 1859A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2108874645,
|
|
|
|
|
|
|
|
ClinVar: RCV000006917
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs and their mother who had been diagnosed with Rapp-Hodgkin syndrome (RHS; 129400), Dianzani et al. (2003) identified a 1-bp deletion (1859delA) in exon 14 of the TP63 gene, causing a frameshift at codon 620 affecting the alpha tail. The mutation was not found in an unaffected sib. The mother's clinical history revealed that she had a slight ankyloblepharon on the right eye at birth which was surgically treated; Dianzani et al. (2003) suggested that ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) and RHS are the same clinical entity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 ANKYLOBLEPHARON-ECTODERMAL DEFECTS-CLEFT LIP/PALATE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
RAPP-HODGKIN SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ILE510THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908845,
|
|
|
|
|
|
|
|
ClinVar: RCV000006918, RCV000006919
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) previously described by Bertola et al. (2000) and in a patient with Rapp-Hodgkin syndrome (RHS; 129400), Bertola et al. (2004) identified a 1529C-to-T transition in exon 12 of the TP63 gene, predicting an ile510-to-thr (I510T) substitution. Both cases were sporadic. Bertola et al. (2004) concluded that AEC and RHS represent variable expression of a single genetic disorder. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 RAPP-HODGKIN SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG545PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908846,
|
|
|
|
|
|
gnomAD: rs121908846,
|
|
|
|
|
|
ClinVar: RCV000006920
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; 129400), Kantaputra et al. (2003) identified heterozygosity for a 1633T-C transition in exon 13 of the TP63 gene, resulting in a ser545-to-pro (S545P) substitution in the fourth helix of the sterile alpha motif (SAM) domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 ADULT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, VAL114MET
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000006921
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with ADULT syndrome (103285), Slavotinek et al. (2005) identified a heterozygous 518G-A transition in exon 4 of the TP63 gene, resulting in a val114-to-met (V114M) substitution. The patient had fifth finger brachydactyly and camptodactyly, ulnar ray hypoplasia, and imperforate anus, suggesting phenotypic overlap with ulnar-mammary syndrome (181450). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 OROFACIAL CLEFT 8</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG313GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908847,
|
|
|
|
|
|
|
|
ClinVar: RCV000006922, RCV002467435
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old Thai girl with orofacial cleft (OFC8; 618149), Leoyklang et al. (2006) found a heterozygous 937A-G transition in exon 8 of the TP63 gene, resulting in an arg313-to-gly (R313G) substitution at a highly conserved residue in the DNA binding domain. The patient had a surgically repaired bilateral complete cleft lip. The mutation was not found in her unaffected parents or in 1,000 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 ADULT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG298GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs113993966,
|
|
|
|
|
|
|
|
ClinVar: RCV000006923, RCV001280741
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Finnish family with ADULT syndrome (103285), Rinne et al. (2006) identified a heterozygous 892C-G transversion in the TP63 gene, resulting in an arg298-to-gly (R298G) substitution. This substitution occurs in the same codon as another variant reported in ADULT syndrome (R298Q; 603273.0014). In vitro functional expression studies showed that the R298G mutation resulted in increased transcription activation, similar to the R298Q mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 SPLIT-HAND/FOOT MALFORMATION 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG97CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908848,
|
|
|
|
|
|
gnomAD: rs121908848,
|
|
|
|
|
|
ClinVar: RCV000006924, RCV001851711, RCV005031401
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Mexican child with isolated unilateral split-hand malformation (SHFM4; 605289), Zenteno et al. (2005) identified a heterozygous 289C-T transition in exon 3 of the TP63 gene, resulting in an arg97-to-cys (R97C) substitution in the transactivation domain. The child also had a small scalp lesion, or aplasia cutis, which may or may not have been related to the TP63 mutation. </p>
|
|
</span>
|
|
</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>.0024 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 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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ADULT SYNDROME, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TP63, ARG227GLN
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<br />
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SNP: rs121908849,
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ClinVar: RCV000006925, RCV000006926, RCV000413620, RCV001390108
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected individuals from 3 unrelated families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), 2 of which were previously reported by O'Quinn et al. (1998), van Bokhoven et al. (2001) identified heterozygosity for a 797G-A transition in the TP63 gene, resulting in an arg227-to-gln (R227Q) substitution. </p><p>Sripathomsawat et al. (2011) provided follow-up of a remotely consanguineous Dutch family with EEC3, previously reported by Maas et al. (1996) and O'Quinn et al. (1998), in which affected members were heterozygous for the R227Q mutation. Twelve newly affected individuals were identified, with marked phenotypic variability. Limb defects were present in 12 of 26 affected members, including 6 with split hand/foot and 1 with mesoaxial polydactyly. Two had cleft lip/palate, and 3 had mild manifestations of this features, such as indentation of the upper vermilion border. One individual had features of the AEC syndrome (106260). Features of ectodermal dysplasia were also variable. Most had blonde, sparse hair with slow growth, thin nails, periorbital hyperpigmentation, and dental caries. Four had hypodontia, and 8 were edentulous on examination. Most notable, 12 of those affected had micturition difficulties, which tended to improve with age, and 1 had defecation difficulties. Sripathomsawat et al. (2011) emphasized that patients with EEC3 should have systematic dental examinations. </p><p>In a mother and daughter with ADULT syndrome (103285), Reisler et al. (2006) identified the R227Q mutation in exon 6 of the TP63 gene and suggested that there may be considerable overlap between the EEC and ADULT syndromes. </p><p>In affected members of 2 unrelated families with EEC syndrome, features of limb-mammary syndrome (LMS; 603543), and severe micturition difficulties, Maclean et al. (2007) identified the R227Q mutation in the TP63 gene. Noting that 4 of the 6 cases/families reported with this mutation had manifested similar urinary symptoms (see van Bokhoven et al., 2001), the authors suggested that this represents a genotype/phenotype correlation. </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>.0025 RAPP-HODGKIN 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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TP63, 1-BP DEL, 1783C
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<br />
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SNP: rs2108874029,
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ClinVar: RCV000006927
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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 mother and daughter with Rapp-Hodgkin syndrome (RHS; 129400) associated with corneal dystrophy and premature menopause, Holder-Espinasse et al. (2007) identified heterozygosity for a 1-bp deletion (1783delC) in the TP63 gene, resulting in a frameshift and a protein that is 22 amino acids longer than wildtype. The authors stated that this was the first report of these associated age-related features in RHS. </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>.0026 ADULT 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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TP63, PRO127LEU
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<br />
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ClinVar: RCV000006928
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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 Dutch mother and daughter with minimal manifestations of ADULT syndrome (103285), van Zelst-Stams and van Steensel (2009) identified heterozygosity for a 380C-T transition in the TP63 gene, resulting in a pro127-to-leu (P127L) substitution at a highly conserved residue in the C-terminal end of the proline-rich domain. The mutation was not found in 100 unrelated Dutch controls. </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>.0027 RAPP-HODGKIN 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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ANKYLOBLEPHARON-ECTODERMAL DEFECTS, CLEFT LIP/PALATE, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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TP63, 11-BP DUP, NT1716
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<br />
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ClinVar: RCV000006929, RCV001794436
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an 11-year-old boy who displayed an overlapping phenotype with features of both ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) and Rapp-Hodgkin syndrome (RHS; 129400), Prontera et al. (2008) identified heterozygosity for an 11-bp duplication (1716dupCTCCCCTTCTC) in exon 14 of the TP63 gene, predicted to result in a protein that is 26 amino acids longer than wildtype. The mutation is located in the transcriptional inhibitory domain (TID) and is predicted to affect only the TP63-alpha isoforms. The patient was born with bilateral ankyloblepharon filiforme adnatum and submucous cleft palate and was diagnosed with AEC syndrome; however, he had only slight erythema of the scalp without infection or erosion or areas of eczematous skin. Upon reevaluation at age 11 years, he showed facial dysmorphism including high frontal hairline, hypoplastic alae nasi, pinched and narrow nose, midface hypoplasia with relative prognathism, and had hypohidrosis and syndactyly, features more suggestive of a diagnosis of RHS. </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>.0028 ECTRODACTYLY, ECTODERMAL DYSPLASIA, AND CLEFT LIP/PALATE SYNDROME 3</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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TP63, ARG227PRO
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<br />
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|
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SNP: rs121908849,
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ClinVar: RCV000023290, RCV004719659
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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 Thai father and his daughter with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Sripathomsawat et al. (2011) identified a heterozygous 680G-C transversion in exon 6 of the TP63 gene, resulting in an arg227-to-pro (R227P) substitution in a highly conserved residue. The mutation was not found in 100 Thai control individuals. The 4-year-old daughter had dry and sparse dark hair, left cleft lip and palate, depressed nasal bridge, slightly dry skin, and thin nails. She had split hands and split right foot, as well as syndactyly of the right fourth and fifth toes. Her father had normal dark hair, dry skin, split right hand, bifid right thumb, and flexion contracture of the distal phalanx of the left index finger. His second toes were small and slender, and he had underdeveloped toenails. The father had significant dental involvement, with enamel hypoplasia, extensive dental caries, hypodontia of the mandibular canines, generalized microdontia, prominent marginal ridges of permanent maxillary incisors, round-shaped permanent molars, and barrel-shaped permanent maxillary central incisors. Although the mutation affected the same residue as a mutation found in a Dutch family with EEC3 and significant micturition difficulties (R227Q; 603273.0024), neither of the Thai patients had micturition problems. Sripathomsawat et al. (2011) emphasized that patients with EEC3 should have systematic dental examinations. </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>.0029 OROFACIAL CLEFT 8</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
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TP63, 2-BP DUP, 819CC
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<br />
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|
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SNP: rs1560277554,
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|
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ClinVar: RCV000710017
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (CLP-1055) in which the proband and his father had orofacial cleft (OFC8; 618149), Basha et al. (2018) identified heterozygosity for a 2-bp duplication (c.819-820dupCC, NM_003722.4) in exon 6 of the TP63 gene, resulting in a frameshift and a premature termination codon (Gln274fsTer4) in the evolutionarily conserved DNA binding domain. mRNA studies demonstrated nonsense-mediated mRNA decay of the mutant allele. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. The son had a unilateral right-sided cleft lip and his father had a unilateral left-sided cleft lip. Neither patient had any symptoms of other TP63 disorders. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 PREMATURE OVARIAN FAILURE 21</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG594TER
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|
|
|
|
|
<br />
|
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|
|
SNP: rs900140738,
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|
|
|
|
|
gnomAD: rs900140738,
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|
|
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|
|
ClinVar: RCV000766166, RCV003159542
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old girl (patient 8) with primary amenorrhea (POF21; 620311), Tucker et al. (2019) identified heterozygosity for a de novo c.1780C-T transition (c.1780C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg594-to-ter (R594X) substitution within the sterile alpha motif, truncating TP63 before the transactivation inhibitory domain. The mutation was not found in her unaffected parents or in public variant databases. </p><p>In a 27-year-old Chinese woman (patient 5) with primary amenorrhea and nonvisualization of the ovaries on ultrasound, Huang et al. (2023) identified heterozygosity for the R594X mutation in the TP63 gene. The authors noted that the R594X variant was present at low minor allele frequency in the gnomAD and ExAC databases (MAFs, 0.00003290 and 0.00007419, respectively). Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the R594X mutant. BN-PAGE analysis suggested that the R594X mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R594X mutant. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 PREMATURE OVARIAN FAILURE 21</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, TRP598TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1560311010,
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|
|
|
|
|
|
|
ClinVar: RCV000766167, RCV003159543
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman (FRA125) with primary amenorrhea (POF21; 620311), Tucker et al. (2019) identified heterozygosity for a c.1794G-A transition (c.1794G-A, NM_003722.4) in exon 14 of the TP63 gene, resulting in a trp598-to-ter (W598X) substitution. Parental DNA status was not reported, but the mutation was not found in public variant databases. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 PREMATURE OVARIAN FAILURE 21</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, ARG97PRO
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|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV002291803, RCV003159546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old woman and her paternal aunt with secondary amenorrhea and atrophic ovaries (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a c.290G-C transversion (c.290G-C, NM_003722.5) in exon 3 of the TP63 gene, resulting in an arg97-to-pro (R97P) substitution at a highly conserved residue within the N-terminal TAD of the TAp63-alpha isoform. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R97P substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63. </p>
|
|
</span>
|
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</div>
|
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 PREMATURE OVARIAN FAILURE 21</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
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|
TP63, ARG647CYS
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<br />
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|
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ClinVar: RCV002291804, RCV003159547
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 27-year-old woman with secondary amenorrhea and atrophic ovaries devoid of follicles (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a paternally inherited c.1939C-T transition (c.1939C-T, NM_003722.5) in exon 14 of the TP63 gene, resulting in an arg647-to-cys (R647C) substitution at a highly conserved residue within the C-terminal TID. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R647C substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63. </p><p>In 3 unrelated Chinese women (patients 8, 9, and 10) with secondary amenorrhea and nonvisualization of the ovaries on ultrasound, Huang et al. (2023) identified heterozygosity for the R647C mutation in the TP63 gene. The R647C variant was not found in the ExAC database, but was present at low minor allele frequency in gnomAD (MAF, 0.00001316). Western blot of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but significantly reduced expression of the R647C mutant. BN-PAGE analysis suggested that the R647C mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R647C mutant. Mice heterozygous for the R647C mutation showed accelerated oocyte loss, reduced fertility, and impaired oocyte quality, but the phenotypes were less severe than mice carrying a mutation that truncated the TID. The authors noted that this was consistent with patients carrying the R647C mutation presenting with secondary amenorrhea. </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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 PREMATURE OVARIAN FAILURE 21</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TP63, 1-BP DEL, 1703A
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003159548
|
|
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|
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</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 32-year-old Chinese woman (patient 4) with primary amenorrhea (POF21; 620311), Huang et al. (2023) identified heterozygosity for a 1-bp deletion (c.1703delA, NM_003722.5) in exon 13 of the TP63 gene, causing a frameshift predicted to result in a premature termination codon (Gln568fsTer3). The mutation was not found in the ExAC or gnomAD databases. Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the Gln568fsTer3 mutant. BN-PAGE analysis suggested that the Gln568fsTer3 mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the Gln568fsTer3 mutant. </p>
|
|
</span>
|
|
</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>.0035 LIMB-MAMMARY SYNDROME, ATYPICAL</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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TP63, ARG643TER
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<br />
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SNP: rs1560311554,
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ClinVar: RCV000760773, RCV003159544
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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 6 affected individuals over 2 generations of a Danish family with an atypical form of limb-mammary syndrome (LMS; 603543), Mathorne et al. (2020) identified heterozygosity for a c.1927C-T transition (c.1927C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg643-to-ter (R643X) substitution within the transactivation inhibitory domain (TID). The mutation segregated with disease in the family and was not found in the gnomAD database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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Akahoshi, K., Sakazume, S., Kosaki, K., Ohashi, H., Fukushima, Y.
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<strong>EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma.</strong>
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<p class="mim-text-font">
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Amiel, J., Bougeard, G., Francannet, C., Raclin, V., Munnich, A., Lyonnet, S., Frebourg, T.
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<strong>TP63 gene mutation in ADULT syndrome.</strong>
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Europ. J. Hum. Genet. 9: 642-645, 2001.
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<strong>Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16.</strong>
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Beaudry, V. G., Pathak, N., Koster, M. I., Attardi, L. D.
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<strong>Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.</strong>
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Am. J. Med. Genet. 149A: 1952-1957, 2009.
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[PubMed: 19353588]
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Benard, J., Douc-Rasy, S., Ahomadegbe, J.-C.
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<strong>TP53 family members and human cancers.</strong>
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Hum. Mutat. 21: 182-191, 2003.
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[PubMed: 12619104]
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[Full Text: https://doi.org/10.1002/humu.10172]
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Bertola, D. R., Kim, C. A., Albano, L. M. J., Scheffer, H., Meijer, R., van Bokhoven, H.
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<strong>Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. (Letter)</strong>
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Clin. Genet. 66: 79-80, 2004.
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[PubMed: 15200513]
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[Full Text: https://doi.org/10.1111/j.0009-9163.2004.00278.x]
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Bertola, D. R., Kim, C. A., Sugayama, S. M. M., Albano, L. M. J., Utagawa, C. Y., Gonzalez, C. H.
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<strong>AEC syndrome and CHAND syndrome: further evidence of clinical overlapping in the ectodermal dysplasias.</strong>
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Pediat. Derm. 17: 218-221, 2000.
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[PubMed: 10886756]
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[Full Text: https://doi.org/10.1046/j.1525-1470.2000.01756.x]
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</p>
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<p class="mim-text-font">
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Borrelli, S., Candi, E., Hu, B., Dolfini, D., Ravo, M., Grober, O. M. V., Weisz, A., Dotto, G. P., Melino, G., Vigano, M. A., Mantovani, R.
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<strong>The p63 target HBP1 is required for skin differentiation and stratification.</strong>
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Cell Death Diff. 17: 1896-1907, 2010.
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[PubMed: 20523354]
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[Full Text: https://doi.org/10.1038/cdd.2010.59]
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</p>
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<li>
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<p class="mim-text-font">
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Bougeard, G., Hadj-Rabia, S., Faivre, L., Sarafan-Vasseur, N., Frebourg, T.
|
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<strong>The Rapp-Hodgkin syndrome results from mutations of the TP63 gene.</strong>
|
|
Europ. J. Hum. Genet. 11: 700-704, 2003.
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[PubMed: 12939657]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201004]
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<li>
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<p class="mim-text-font">
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Brunner, H. G., Hamel, B. C. J., van Bokhoven, H.
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<strong>P63 gene mutations and human developmental syndromes.</strong>
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Am. J. Med. Genet. 112: 284-290, 2002.
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[PubMed: 12357472]
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[Full Text: https://doi.org/10.1002/ajmg.10778]
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</p>
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<li>
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<p class="mim-text-font">
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Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H.
|
|
<strong>Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.</strong>
|
|
Cell 99: 143-153, 1999.
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[PubMed: 10535733]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81646-3]
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</p>
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<li>
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<p class="mim-text-font">
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Conforti, F., Yang, A. L., Piro, M. C., Mellone, M., Terrinoni, A., Candi, E., Tucci, P., Thomas, G. J., Knight, R. A., Melino, G., Sayan, B. S.
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<strong>PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21(WAF1) and p63.</strong>
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Oncogene 32: 4758-4765, 2013.
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[PubMed: 23128396]
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[Full Text: https://doi.org/10.1038/onc.2012.497]
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</p>
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<li>
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<p class="mim-text-font">
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Deutsch, G. B., Zielonka, E. M., Coutandin, D., Weber, T. A., Schafer, B., Hannewald, J., Luh, L. M., Durst, F. G., Ibrahim, M., Hoffmann, J., Niesen, F. H., Senturk, A., Kunkel, H., Brutschy, B., Schleiff, E., Knapp, S., Acker-Palmer, A., Grez, M., McKeon, F., Dotsch, V.
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<strong>DNA damage in oocytes induces a switch of the quality control factor TAp63-alpha from dimer to tetramer.</strong>
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Cell 144: 566-576, 2011.
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[PubMed: 21335238]
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[Full Text: https://doi.org/10.1016/j.cell.2011.01.013]
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</p>
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<li>
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<p class="mim-text-font">
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Di Iorio, E., Barbaro, V., Ruzza, A., Ponzin, D., Pellegrini, G., De Luca, M.
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<strong>Isoforms of delta-N-p63 and the migration of ocular limbal cells in human corneal regeneration.</strong>
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Proc. Nat. Acad. Sci. 102: 9523-9528, 2005.
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[PubMed: 15983386]
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[Full Text: https://doi.org/10.1073/pnas.0503437102]
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</p>
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<p class="mim-text-font">
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Dianzani, I., Garelli, E., Gustavsson, P., Carando, A., Gustafsson, B., Dahl, N., Anneren, G.
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<strong>Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene.</strong>
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J. Med. Genet. 40: e133, 2003. Note: Electronic Article.
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[PubMed: 14684701]
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[Full Text: https://doi.org/10.1136/jmg.40.12.e133]
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<p class="mim-text-font">
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Duijf, P. H. G., Vanmolkot, K. R. J., Propping, P., Friedl, W., Krieger, E., McKeon, F., Dotsch, V., Brunner, H. G., van Bokhoven, H.
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<strong>Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63.</strong>
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Hum. Molec. Genet. 11: 799-804, 2002.
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[PubMed: 11929852]
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</p>
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<li>
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<p class="mim-text-font">
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|
Flores, E. R., Tsai, K. Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T.
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|
<strong>p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.</strong>
|
|
Nature 416: 560-564, 2002. Note: Expression of Concern: Nature 627: E10, 2024.
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[PubMed: 11932750]
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[Full Text: https://doi.org/10.1038/416560a]
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<p class="mim-text-font">
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Gershoni-Baruch, R., Goldscher, D., Hochberg, Z.
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<strong>Ectrodactyly-ectodermal dysplasia-clefting syndrome and hypothalamo-pituitary insufficiency.</strong>
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Am. J. Med. Genet. 68: 168-172, 1997.
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[PubMed: 9028452]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(19970120)68:2<168::aid-ajmg9>3.0.co;2-l]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Guazzarotti, L., Caprio, C., Rinne, T. K., Bosoni, M., Pattarino, G., Mauri, S., Tadini, G. L., van Bokhoven, H., Zuccotti, G. V.
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<strong>Limb-mammary syndrome (LMS) associated with internal female genitalia dysgenesia: a new genotype/phenotype correlation?</strong>
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Am. J. Med. Genet. 146A: 2001-2004, 2008.
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[PubMed: 18627043]
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[Full Text: https://doi.org/10.1002/ajmg.a.32371]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., Sidransky, D.
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<strong>AIS is an oncogene amplified in squamous cell carcinoma.</strong>
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Proc. Nat. Acad. Sci. 97: 5462-5467, 2000.
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[PubMed: 10805802]
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[Full Text: https://doi.org/10.1073/pnas.97.10.5462]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Holder-Espinasse, M., Martin-Coignard, D., Escande, F., Manouvrier-Hanu, S.
|
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<strong>A new mutation in TP63 is associated with age-related pathology.</strong>
|
|
Europ. J. Hum. Genet. 15: 1115-1120, 2007.
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[PubMed: 17609671]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201888]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Huang, C., Zhao, S., Yang, Y., Guo, T., Ke, H., Mi, X., Qin, Y., Chen, Z. J., Zhao, S.
|
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<strong>TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.</strong>
|
|
J. Clin. Invest. 133: e162315, 2023.
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[PubMed: 36856110]
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[Full Text: https://doi.org/10.1172/JCI162315]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P.
|
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<strong>Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.</strong>
|
|
Am. J. Hum. Genet. 67: 59-66, 2000.
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[PubMed: 10839977]
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[Full Text: https://doi.org/10.1086/302972]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kantaputra, P. N., Hamada, T., Kumchai, T., McGrath, J. A.
|
|
<strong>Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia.</strong>
|
|
J. Dent. Res. 82: 433-437, 2003.
|
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|
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[PubMed: 12766194]
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[Full Text: https://doi.org/10.1177/154405910308200606]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Keyes, W. M., Vogel, H., Koster, M. I., Guo, X., Qi, Y., Petherbridge, K. M., Roop, D. R., Bradley, A., Mills, A. A.
|
|
<strong>p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 8435-8440, 2006.
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[PubMed: 16714381]
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[Full Text: https://doi.org/10.1073/pnas.0602477103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kosaki, R., Naito, Y., Torii, C., Takahashi, T., Nakajima, T., Kosaki, K.
|
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<strong>Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation. (Letter)</strong>
|
|
Am. J. Med. Genet. 146A: 2574-2577, 2008.
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[PubMed: 18792980]
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[Full Text: https://doi.org/10.1002/ajmg.a.32415]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Leoyklang, P., Siriwan, P., Shotelersuk, V.
|
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<strong>A mutation of the p63 gene in non-syndromic cleft lip. (Letter)</strong>
|
|
J. Med. Genet. 43: e28, 2006. Note: Electronic Article.
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[PubMed: 16740912]
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[Full Text: https://doi.org/10.1136/jmg.2005.036442]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E., Mills, A. A., Morasso, M. I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G. R.
|
|
<strong>Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.</strong>
|
|
Development 135: 1377-1388, 2008.
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[PubMed: 18326838]
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[Full Text: https://doi.org/10.1242/dev.011759]
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</p>
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Bao Lige - updated : 10/05/2023<br>Marla J. F. O'Neill - updated : 04/04/2023<br>Marla J. F. O'Neill - updated : 04/04/2023<br>Bao Lige - updated : 04/30/2020<br>Carol A. Bocchini - updated : 10/14/2018<br>Ada Hamosh - updated : 2/2/2016<br>Ada Hamosh - updated : 2/2/2016<br>Paul J. Converse - updated : 12/23/2015<br>Patricia A. Hartz - updated : 11/17/2014<br>Patricia A. Hartz - updated : 12/19/2013<br>Patricia A. Hartz - updated : 10/3/2012<br>Patricia A. Hartz - updated : 4/26/2012<br>Cassandra L. Kniffin - updated : 1/5/2012<br>Marla J. F. O'Neill - updated : 7/12/2011<br>Patricia A. Hartz - updated : 5/5/2011<br>Ada Hamosh - updated : 12/27/2010<br>Marla J. F. O'Neill - updated : 6/9/2010<br>Marla J. F. O'Neill - updated : 1/22/2010<br>Marla J. F. O'Neill - updated : 12/4/2009<br>Marla J. F. O'Neill - updated : 8/17/2009<br>Marla J. F. O'Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 7/18/2008<br>Patricia A. Hartz - updated : 5/28/2008<br>Ada Hamosh - updated : 5/21/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Marla J. F. O'Neill - updated : 4/13/2007<br>Marla J. F. O'Neill - updated : 2/5/2007<br>Ada Hamosh - updated : 2/1/2007<br>Cassandra L. Kniffin - updated : 10/2/2006<br>Cassandra L. Kniffin - updated : 9/21/2006<br>Patricia A. Hartz - updated : 8/15/2006<br>Victor A. McKusick - updated : 6/27/2006<br>Cassandra L. Kniffin - updated : 10/21/2005<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Patricia A. Hartz - updated : 8/15/2005<br>Marla J. F. O'Neill - updated : 5/5/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 1/22/2004<br>Victor A. McKusick - updated : 8/5/2003<br>George E. Tiller - updated : 10/29/2002<br>Victor A. McKusick - updated : 10/16/2002<br>Victor A. McKusick - updated : 7/17/2002<br>Ada Hamosh - updated : 4/9/2002<br>Michael B. Petersen - updated : 11/29/2001<br>George E. Tiller - updated : 4/18/2001<br>Victor A. McKusick - updated : 9/8/2000<br>Ada Hamosh - updated : 8/14/2000<br>Victor A. McKusick - updated : 7/25/2000<br>Stylianos E. Antonarakis - updated : 11/11/1999<br>Victor A. McKusick - updated : 4/8/1999
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