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Entry
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- *601309 - PATCHED 1; PTCH1
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- OMIM
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<div class="container hidden-print">
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<div id="mimAlertBanner">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601309</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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>
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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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/601309">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000185920;t=ENST00000331920" 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=5727" 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=601309" 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=ENSG00000185920;t=ENST00000331920" 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_000264,NM_001083602,NM_001083603,NM_001083604,NM_001083605,NM_001083606,NM_001083607,NM_001354918,NM_001354919,NR_149061" 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_000264" 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=601309" 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=03200&isoform_id=03200_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/PTCH1" 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/1335864,1381236,28175594,34530418,38489134,56378003,56378005,56378007,56378009,56378011,62088570,76559762,76559766,76559768,76559770,119613037,119613038,126364298,126364300,134254432,134254435,134254446,134254450,134254452,134254466,134254468,160415977,1179780964,1179780966,1237937711,1237937983,1843476470,1843476472" 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/Q13635" 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=5727" 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=ENSG00000185920;t=ENST00000331920" 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=PTCH1" 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=PTCH1" 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+5727" 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/PTCH1" 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:5727" 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/5727" 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=chr9&hgg_gene=ENST00000437951.6&hgg_start=95442980&hgg_end=95516971&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:9585" 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:9585" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ptch1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601309[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=601309[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/PTCH1/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/ENSG00000185920" 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=PTCH1" 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=PTCH1" 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=PTCH1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.cybergene.se/cgi-bin/w3-msql/ptchbase/index.html" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PTCH1&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/PA33937" 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:9585" 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/FBgn0003892.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:105373" 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/PTCH1#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:105373" 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/5727/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=5727" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004208;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004208 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00004210;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00004210 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-196" 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:5727" 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=PTCH1&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> 69408002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601309
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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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PATCHED 1; PTCH1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
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PATCHED, DROSOPHILA, HOMOLOG OF, 1<br />
|
|
PTCH<br />
|
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PTC
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PTCH1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PTCH1</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>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/331?start=-3&limit=10&highlight=331">9q22.32</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:95442980-95516971&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'})">9:95,442,980-95,516,971</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<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>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=605462,109400,610828" 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>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/331?start=-3&limit=10&highlight=331">
|
|
9q22.32
|
|
</a>
|
|
</span>
|
|
</td>
|
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<td>
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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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<p>The Drosophila 'Patched' (ptc) gene encodes a transmembrane protein that represses transcription in specific cells of genes encoding members of the TGF-beta (see <a href="/entry/190180">190180</a>) and Wnt (<a href="/entry/164820">164820</a>) families of signaling proteins. Vertebrate homologs of ptc have been identified in mice, chickens, and zebrafish. <a href="#23" class="mim-tip-reference" title="Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, E. H., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., Scott, M. P. <strong>Human homolog of Patched, a candidate gene for the basal cell nevus syndrome.</strong> Science 272: 1668-1671, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8658145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8658145</a>] [<a href="https://doi.org/10.1126/science.272.5268.1668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8658145">Johnson et al. (1996)</a> reported the isolation and mapping of the human homolog of the Drosophila ptc gene. They cloned the human PTC gene by screening a human lung cDNA library with mouse ptc cDNA clones. They assembled 5.1 kb of contiguous sequence containing a 4.5-kb open reading frame that encodes a 1,447-amino acid protein. The predicted amino acid sequence has 96% identity to mouse and a 40% identity to Drosophila ptc proteins. The human PTC protein is predicted to contain 12 hydrophobic membrane-spanning domains and 2 large hydrophilic extracellular loops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8658145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> likewise isolated a human sequence with strong homology to the Drosophila segment polarity gene 'Patched' from a YAC and cosmid contig of the nevoid basal cell carcinoma (NBCCS) region on chromosome 9q22.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR, <a href="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> identified 7 human PTCH transcripts that differ through their use of 5 possible first exons and alternative splicing involving 2 of the possible first exons. These mRNAs encode 4 PTCH proteins with different N termini, including one, designated PTCH-S, that is N-terminally truncated and lacks the first transmembrane domain. RT-PCR detected expression of PTCH in all tissues examined, with lowest levels in heart and liver. Expression of individual PTCH transcripts was tissue specific. <a href="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> also identified multiple Ptch splice variants in mouse. During mouse embryonic development, expression of Ptch was highest at embryonic day 10.5, and it declined thereafter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15780749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>To assess the role of Ptc in cell physiology and development, <a href="#28" class="mim-tip-reference" title="Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M., Tabin, C. J. <strong>Biochemical evidence that Patched is the hedgehog receptor.</strong> Nature 384: 176-179, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906794</a>] [<a href="https://doi.org/10.1038/384176a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906794">Marigo et al. (1996)</a> expressed the chick Patched gene in Xenopus laevis oocytes (oocytes do not express endogenous Ptc). Protein of the size expected for Ptc was detected 48 hours after injection. They then performed binding assays on injected, uninjected, and control-injected oocytes using the N-terminal fragment (N-Shh) of human Sonic hedgehog protein (SHH; <a href="/entry/600725">600725</a>). The binding assay showed that labeled N-Shh protein could bind to Ptc-injected oocytes, but not to the control oocytes. Injected oocytes bound human N-Shh produced in E. coli and mouse N-Shh produced in the baculovirus system. <a href="#28" class="mim-tip-reference" title="Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M., Tabin, C. J. <strong>Biochemical evidence that Patched is the hedgehog receptor.</strong> Nature 384: 176-179, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906794</a>] [<a href="https://doi.org/10.1038/384176a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906794">Marigo et al. (1996)</a> demonstrated direct interaction between Ptc and Shh using coimmunoprecipitation studies. They also showed that the 2 extracellular loops of the Ptc protein are necessary for binding and that binding also requires that the Ptc protein be glycosylated. <a href="#28" class="mim-tip-reference" title="Marigo, V., Davey, R. A., Zuo, Y., Cunningham, J. M., Tabin, C. J. <strong>Biochemical evidence that Patched is the hedgehog receptor.</strong> Nature 384: 176-179, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906794</a>] [<a href="https://doi.org/10.1038/384176a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906794">Marigo et al. (1996)</a> proposed that Ptc does not carry out signaling to the cell directly but that an additional molecule is involved, namely the 7-transmembrane protein 'Smoothened ' (SMO; <a href="/entry/601500">601500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8906794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Independently and simultaneously, <a href="#42" class="mim-tip-reference" title="Stone, D. M., Hynes, M., Armanini, M., Swanson, T. A., Gu, Q., Johnson, R. L., Scott, M. P., Pennica, D., Goddard, A., Phillips, H., Noll, M., Hooper, J. E., de Sauvage, F., Rosenthal, A. <strong>The tumour-suppressor gene Patched encodes a candidate receptor for Sonic hedgehog.</strong> Nature 384: 129-134, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906787</a>] [<a href="https://doi.org/10.1038/384129a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906787">Stone et al. (1996)</a> concluded that the Ptc gene encodes a candidate receptor for Shh by showing that epitope-tagged N-Shh binds specifically to human embryonic kidney 293 cells expressing mouse Ptc. Ptc also could be immunoprecipitated by N-Shh-IgG. The authors calculated a K(d) of 460 picoM for binding of N-Shh and mouse Ptc. By expression of genes in 293 cells with subsequent lysis and immunoprecipitation, <a href="#42" class="mim-tip-reference" title="Stone, D. M., Hynes, M., Armanini, M., Swanson, T. A., Gu, Q., Johnson, R. L., Scott, M. P., Pennica, D., Goddard, A., Phillips, H., Noll, M., Hooper, J. E., de Sauvage, F., Rosenthal, A. <strong>The tumour-suppressor gene Patched encodes a candidate receptor for Sonic hedgehog.</strong> Nature 384: 129-134, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906787</a>] [<a href="https://doi.org/10.1038/384129a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906787">Stone et al. (1996)</a> showed that Ptc, Smo, and Shh form a physical complex in vivo and that a Smo-Shh complex does not form in the absence of Ptc. They proposed that the hedgehog system may provide mitogenic or differentiative signals to basal cells in the skin throughout life. They also raised the possibility that BCNS and BCC might result from constitutive activation of Smo which becomes oncogenic after its release from inhibition by Ptc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8906787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>On the basis of their studies in Drosophila, <a href="#9" class="mim-tip-reference" title="Chen, Y., Struhl, G. <strong>Dual roles for Patched in sequestering and transducing hedgehog.</strong> Cell 87: 553-563, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8898207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8898207</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81374-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8898207">Chen and Struhl (1996)</a> presented evidence that Ptc acts as a receptor for hedgehog (Hh) proteins. They suggested a novel signal transduction mechanism in which Hh proteins bind to Ptc or to a Ptc-Smo complex and thereby induces Smo activity. Their results showed further that Ptc limits the range of Hh action and that the high levels of Ptc induced by Hh serve to sequester any free Hh and thereby create a barrier to its further movement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8898207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and other human tumors are associated with mutations that activate the protooncogene 'Smoothened' or that inactivate the tumor suppressor 'Patched.' Smoothened and Patched mediate the cellular response to the hedgehog secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the hedgehog response pathway. <a href="#45" class="mim-tip-reference" title="Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., Beachy, P. A. <strong>Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.</strong> Nature 406: 1005-1009, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10984056</a>] [<a href="https://doi.org/10.1038/35023008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10984056">Taipale et al. (2000)</a> showed that the plant-derived teratogen cyclopamine, which inhibits the hedgehog response, is a potential mechanism-based therapeutic agent for treatment of these tumors. <a href="#45" class="mim-tip-reference" title="Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., Beachy, P. A. <strong>Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.</strong> Nature 406: 1005-1009, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10984056</a>] [<a href="https://doi.org/10.1038/35023008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10984056">Taipale et al. (2000)</a> showed that cyclopamine or synthetic derivatives with improved potency block activation of the hedgehog response pathway and abnormal cell growth associated with both types of oncogenic mutation. <a href="#45" class="mim-tip-reference" title="Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., Beachy, P. A. <strong>Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.</strong> Nature 406: 1005-1009, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10984056</a>] [<a href="https://doi.org/10.1038/35023008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10984056">Taipale et al. (2000)</a> concluded that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10984056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bale, A. E., Yu, K.-P. <strong>The hedgehog pathway and basal cell carcinomas.</strong> Hum. Molec. Genet. 10: 757-762, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257109</a>] [<a href="https://doi.org/10.1093/hmg/10.7.757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257109">Bale and Yu (2001)</a> reviewed the hedgehog pathway and its disruption as a basis for basal cell carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#46" class="mim-tip-reference" title="Taipale, J., Cooper, M. K., Maiti, T., Beachy, P. A. <strong>Patched acts catalytically to suppress the activity of Smoothened.</strong> Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192414</a>] [<a href="https://doi.org/10.1038/nature00989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192414">Taipale et al. (2002)</a> reported that Ptc and Smo are not significantly associated with hedgehog-responsive cells and that free Ptc (unbound by hedgehog) acts substoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a 12-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters. <a href="#46" class="mim-tip-reference" title="Taipale, J., Cooper, M. K., Maiti, T., Beachy, P. A. <strong>Patched acts catalytically to suppress the activity of Smoothened.</strong> Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192414</a>] [<a href="https://doi.org/10.1038/nature00989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192414">Taipale et al. (2002)</a> demonstrated that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. <a href="#46" class="mim-tip-reference" title="Taipale, J., Cooper, M. K., Maiti, T., Beachy, P. A. <strong>Patched acts catalytically to suppress the activity of Smoothened.</strong> Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192414</a>] [<a href="https://doi.org/10.1038/nature00989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12192414">Taipale et al. (2002)</a> suggested that the Ptc tumor suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>During early development in vertebrates, SHH is produced by the notochord and the floor plate. A ventrodorsal gradient of SHH directs ventrodorsal patterning of the neural tube. However, SHH is also required for the survival of neuroepithelial cells. <a href="#48" class="mim-tip-reference" title="Thibert, C., Teillet, M.-A., Lapointe, F., Mazelin, L., Le Douarin, N. M., Mehlen, P. <strong>Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog.</strong> Science 301: 843-846, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907805</a>] [<a href="https://doi.org/10.1126/science.1085405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907805">Thibert et al. (2003)</a> demonstrated that PTC induces apoptotic cell death unless its ligand SHH is present to block the signal. Moreover, the blockade of Ptc-induced cell death partly rescues the chick spinal cord defect provoked by Shh deprivation. <a href="#48" class="mim-tip-reference" title="Thibert, C., Teillet, M.-A., Lapointe, F., Mazelin, L., Le Douarin, N. M., Mehlen, P. <strong>Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog.</strong> Science 301: 843-846, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907805</a>] [<a href="https://doi.org/10.1126/science.1085405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907805">Thibert et al. (2003)</a> concluded that the proapoptotic activity of unbound PTC and the positive effect of SHH-bound PTC on cell differentiation probably cooperate to achieve the appropriate spinal cord development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Casali, A., Struhl, G. <strong>Reading the hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein.</strong> Nature 431: 76-80, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15300262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15300262</a>] [<a href="https://doi.org/10.1038/nature02835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15300262">Casali and Struhl (2004)</a> demonstrated that a cell's measure of ambient Hh concentration is not determined solely by the number of active (unliganded) Ptc molecules. Instead, they found that Hh-bound Ptc can titrate the inhibitory action of unbound Ptc. Furthermore, this effect is sufficient to allow normal reading of the Hh gradient in the presence of a form of Ptc that cannot bind the ligand but retains its ability to inhibit Smo. <a href="#6" class="mim-tip-reference" title="Casali, A., Struhl, G. <strong>Reading the hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein.</strong> Nature 431: 76-80, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15300262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15300262</a>] [<a href="https://doi.org/10.1038/nature02835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15300262">Casali and Struhl (2004)</a> concluded that their results supported a model in which the ratio of bound to unbound Ptc molecules determines the cellular response to Hh. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15300262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Chen, W., Ren, X.-R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., Lefkowitz, R. J. <strong>Activity-dependent internalization of Smoothened mediated by beta-arrestin 2 and GRK2.</strong> Science 306: 2257-2260, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618519</a>] [<a href="https://doi.org/10.1126/science.1104135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15618519">Chen et al. (2004)</a> found that 2 molecules interact with mammalian Smo in an activation-dependent manner: G protein-coupled receptor kinase-2 (GRK2; <a href="/entry/109635">109635</a>) leads to phosphorylation of Smo, and beta-arrestin-2 (ARRB2; <a href="/entry/107941">107941</a>) fused to green fluorescent protein interacts with Smo. These 2 processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits association of Arrb2 with Smo, and this inhibition is relieved in cells treated with Shh (<a href="/entry/600725">600725</a>). A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by Grk2 and interaction of Arrb2 with Smo. <a href="#8" class="mim-tip-reference" title="Chen, W., Ren, X.-R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., Lefkowitz, R. J. <strong>Activity-dependent internalization of Smoothened mediated by beta-arrestin 2 and GRK2.</strong> Science 306: 2257-2260, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618519</a>] [<a href="https://doi.org/10.1126/science.1104135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15618519">Chen et al. (2004)</a> suggested that Arrb2 and Grk2 are thus potential mediators of signaling by activated Smo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15618519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> demonstrated that GLI1 (<a href="/entry/165220">165220</a>) regulated PTCH expression. GLI1 induced the expression of individual PTCH transcripts in a cell type-specific manner. <a href="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> identified several GLI1-binding sites in the PTCH promoter region, and they showed that GLI1 interacted directly with the promoter region by electrophoretic mobility shift assay and chromatin immunoprecipitation. The longer PTCH isoforms, which interacted strongly with GLI1 in vitro, induced apoptosis in transfected human embryonic kidney cells, but the shortest isoform, PTCH-S, did not. <a href="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> determined that PTCH-S was much less stable than the longer isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15780749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Rohatgi, R., Milenkovic, L., Scott, M. P. <strong>Patched1 regulates hedgehog signaling at the primary cilium.</strong> Science 317: 372-376, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17641202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17641202</a>] [<a href="https://doi.org/10.1126/science.1139740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17641202">Rohatgi et al. (2007)</a> investigated the role of primary cilia in the regulation of PTCH1, the receptor for SHH. In mammalian cells, PTCH1 localized to cilia and inhibited Smoothened (SMO; <a href="/entry/601500">601500</a>) by preventing its accumulation within cilia. When SHH bound to PTCH1, PTCH1 left the cilia, leading to accumulation of SMO and activation of signaling. Thus, <a href="#40" class="mim-tip-reference" title="Rohatgi, R., Milenkovic, L., Scott, M. P. <strong>Patched1 regulates hedgehog signaling at the primary cilium.</strong> Science 317: 372-376, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17641202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17641202</a>] [<a href="https://doi.org/10.1126/science.1139740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17641202">Rohatgi et al. (2007)</a> concluded that primary cilia sense SHH and transduce signals that play critical roles in development, carcinogenesis, and stem cell function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17641202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 X-gal staining of Ptch1 +/- mice carrying a LacZ knockin null allele of Ptch1, <a href="#27" class="mim-tip-reference" title="Mak, K. K., Bi, Y., Wan, C., Chuang, P.-T., Clemens, T., Young, M., Yang, Y. <strong>Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression.</strong> Dev. Cell 14: 674-688, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18477451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18477451</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.02.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18477451">Mak et al. (2008)</a> found that Ptch1 was expressed in the perichondrium at postnatal day 5, and that expression progressively decreased as osteoblasts became more mature in the cortical and trabecular bone. There was no detectable staining in osteocytes. Ptch1 was also expressed in the calvarial osteoblasts of both postnatal day-5 and 1-year-old Ptch1 +/- mice, and expression was reduced as osteoblasts matured and grew further way from the suture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18477451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Gao, B., Hu, J., Stricker, S., Cheung, M., Ma, G., Law, K. F., Witte, F., Briscoe, J., Mundlos, S., He, L., Cheah, K. S. E., Chan, D. <strong>A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range.</strong> Nature 458: 1196-1200, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252479</a>] [<a href="https://doi.org/10.1038/nature07862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19252479">Gao et al. (2009)</a> showed that the E95K mutation in IHH (<a href="/entry/600726#0001">600726.0001</a>) resulting in brachydactyly type 1 (BDA1; <a href="/entry/112500">112500</a>) impairs the interaction of IHH with PTCH1 and HIP1 (HHIP; <a href="/entry/606178">606178</a>). This was consistent with the findings of <a href="#30" class="mim-tip-reference" title="McLellan, J. S., Zheng, X., Hauk, G., Ghirlando, R., Beachy, P. A., Leahy, D. J. <strong>The mode of hedgehog binding to Ihog homologues is not conserved across different phyla.</strong> Nature 455: 979-983, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18794898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18794898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18794898[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/nature07358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18794898">McLellan et al. (2008)</a> showing that IHH mutations resulting in BDA1 cluster in a calcium-binding site essential for the interaction with its receptor and cell surface partners. Furthermore, <a href="#17" class="mim-tip-reference" title="Gao, B., Hu, J., Stricker, S., Cheung, M., Ma, G., Law, K. F., Witte, F., Briscoe, J., Mundlos, S., He, L., Cheah, K. S. E., Chan, D. <strong>A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range.</strong> Nature 458: 1196-1200, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252479</a>] [<a href="https://doi.org/10.1038/nature07862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19252479">Gao et al. (2009)</a> showed that in a mouse model that recapitulated the E95K mutation there was a change in the potency and range of signaling. The mice had digital abnormalities consistent with the human disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19252479+18794898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Znf431 (<a href="/entry/619505">619505</a>) directly suppressed Ptch1 basal expression by binding to 3 response elements in the promoter of Ptch1 variant-1b in mouse MPLB cells. Znf431 also repressed the cellular response to Hh signaling by repressing expression of Hh signal components. The Hh signaling response was decreased in Znf431-overexpressing cells, whereas it was elevated in Znf431-knockdown cells.</p><p>In their review, <a href="#22" class="mim-tip-reference" title="Huang, G. J., He, Z., Ma, L. <strong>ZFP932 suppresses cellular hedgehog response and Patched1 transcription.</strong> Vitam. Horm. 88: 309-332, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22391310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22391310</a>] [<a href="https://doi.org/10.1016/B978-0-12-394622-5.00014-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22391310">Huang et al. (2012)</a> stated that Znf431, which they called Zfp932, binds to the promoter region of Ptch1 variant-1b through its zinc fingers. Crystallographic studies showed that each zinc finger binds to 3 bp in the DNA sequence and that Zfp932 uses 2 of its 15 zinc fingers when binding to the Ptch1 promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22391310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 centrosome is essential for cytotoxic T lymphocyte function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunologic synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog signaling. Lymphocytes do not form primary cilia, but <a href="#13" class="mim-tip-reference" title="de la Roche, M., Ritter, A. T., Angus, K. L., Dinsmore, C., Earnshaw, C. H., Reiter, J. F., Griffiths, G. M. <strong>Hedgehog signaling controls T cell killing at the immunological synapse.</strong> Science 342: 1247-1250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24311692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24311692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24311692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1244689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24311692">de la Roche et al. (2013)</a> found that Hedgehog signaling plays an important role in cytotoxic T lymphocyte killing. T cell receptor activation, which 'prearms' cytotoxic T lymphocytes with cytotoxic granules, also initiated Hedgehog signaling through IHH, PTCH1, and SMOH (<a href="/entry/601500">601500</a>), which are localized on intracellular vesicles that polarize toward the immunologic synapse. Hedgehog pathway activation occurred intracellularly and triggered RAC1 (<a href="/entry/602048">602048</a>) synthesis. These events 'prearmed' cytotoxic T lymphocytes for action by promoting the actin remodeling required for centrosome polarization and granule release. <a href="#13" class="mim-tip-reference" title="de la Roche, M., Ritter, A. T., Angus, K. L., Dinsmore, C., Earnshaw, C. H., Reiter, J. F., Griffiths, G. M. <strong>Hedgehog signaling controls T cell killing at the immunological synapse.</strong> Science 342: 1247-1250, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24311692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24311692</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24311692[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1244689" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24311692">De la Roche et al. (2013)</a> concluded that Hedgehog signaling plays a role in cytotoxic T lymphocyte function and that the immunologic synapse may represent a modified cilium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24311692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Cooper, K. L., Sears, K. E., Uygur, A., Maier, J., Baczkowski, K.-S., Brosnahan, M., Antczak, D., Skidmore, J. A., Tabin, C. J. <strong>Patterning and post-patterning modes of evolutionary digit loss in mammals.</strong> Nature 511: 41-45, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990742[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/nature13496" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990742">Cooper et al. (2014)</a> showed that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the odd-toed jerboa (Dipus sagitta) and horse and the even-toed camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms, including downregulation of Ptch1 expression, but there is no increase in cell death. <a href="#11" class="mim-tip-reference" title="Cooper, K. L., Sears, K. E., Uygur, A., Maier, J., Baczkowski, K.-S., Brosnahan, M., Antczak, D., Skidmore, J. A., Tabin, C. J. <strong>Patterning and post-patterning modes of evolutionary digit loss in mammals.</strong> Nature 511: 41-45, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990742[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/nature13496" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990742">Cooper et al. (2014)</a> concluded that these data demonstrated remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphologic convergence, particularly within the artiodactyl lineage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Lopez-Rios, J., Duchesne, A., Speziale, D., Andrey, G., Peterson, K. A., Germann, P., Unal, E., Liu, J., Floriot, S., Barbey, S., Gallard, Y., Muller-Gerbl, M., and 11 others. <strong>Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs.</strong> Nature 511: 46-51, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990743</a>] [<a href="https://doi.org/10.1038/nature13289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990743">Lopez-Rios et al. (2014)</a> analyzed bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH; <a href="/entry/600725">600725</a>) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded Shh signaling during bovine handplate development. <a href="#26" class="mim-tip-reference" title="Lopez-Rios, J., Duchesne, A., Speziale, D., Andrey, G., Peterson, K. A., Germann, P., Unal, E., Liu, J., Floriot, S., Barbey, S., Gallard, Y., Muller-Gerbl, M., and 11 others. <strong>Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs.</strong> Nature 511: 46-51, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990743</a>] [<a href="https://doi.org/10.1038/nature13289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990743">Lopez-Rios et al. (2014)</a> concluded that their study provided a molecular explanation for the loss of digit asymmetry in bovine limb buds, and suggested that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using chromatin immunoprecipitation analysis, <a href="#7" class="mim-tip-reference" title="Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P. <strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong> Genome Res. 26: 474-485, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26893459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26893459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26893459[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/10.1101/gr.196048.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26893459">Chassaing et al. (2016)</a> found that Sox2 (<a href="/entry/184429">184429</a>) bound to a sequence within intron 15 of the mouse Ptch1 gene. Suppression of sox2 expression in zebrafish upregulated ptch1 expression and resulted in reduced eye and retina size. Knockdown of ptch1 in zebrafish also caused ocular defects, including reduced eye size. Reduced ptch1 protein in zebrafish led to overactive SHH signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26893459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> defined the intron-exon boundaries of the PTC gene and reported that the PTC gene contains 23 exons spanning approximately 34 kb. They noted that there are at least 3 different forms of the PTC protein present in mammalian cells; the ancestral form and 2 human forms. The first in-frame methionine codon for one of the forms is in the third exon. The other human form of PTC contains an open reading frame that extends through to the 5-prime end and may be initiated by upstream sequences. <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> pointed out that the identification of several potential forms of the PTC protein provides a mechanism whereby a single PTC gene could play a role in different pathways. They stressed that determination of the regulation of different splice forms of PTC mRNA may shed light on the apparent role of the gene in embryonic development and growth control in adult cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" class="mim-tip-reference" title="Nagao, K., Toyoda, M., Takeuchi-Inoue, K., Fujii, K., Yamada, M., Miyashita, T. <strong>Identification and characterization of multiple isoforms of a murine and human tumor suppressor, Patched, having distinct first exons.</strong> Genomics 85: 462-471, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780749</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.11.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780749">Nagao et al. (2005)</a> determined that the PTCH gene contains 5 alternative first exons in addition to the other 22 exons. The PTCH gene covers about 70 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15780749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#18" class="mim-tip-reference" title="Gong, X., Qian, H., Cao, P., Zhao, X., Zhou, Q., Lei, J., Yan, N. <strong>Structural basis for the recognition of Sonic Hedgehog by human Patched1.</strong> Science 361: eaas8935, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29954986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29954986</a>] [<a href="https://doi.org/10.1126/science.aas8935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29954986">Gong et al. (2018)</a> reported the cryoelectron microscopy structures of human PTCH1 alone and in complex with the N-terminal domain of human Sonic hedgehog (SHH; <a href="/entry/600725">600725</a>) at resolutions of 3.9 and 3.6 angstroms, respectively. PTCH1 comprises 2 interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments, with transmembrane segments 2 to 6 constituting the sterol-sensing domain. Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the sterol-sensing domain. Structure-guided mutational analysis showed that interaction between the N terminus of SHH and PTCH1 is steroid-dependent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29954986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Qi, X., Schmiege, P., Coutavas, E., Wang, J., Li, X. <strong>Structures of human Patched and its complex with native palmitoylated sonic hedgehog.</strong> Nature 560: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29995851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29995851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29995851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0308-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29995851">Qi et al. (2018)</a> reported the cryoelectron microscopy structures of human PTCH1 alone and in complex with the N-terminal domain of 'native' SHH (SHH-N), which has both a C-terminal cholesterol and an N-terminal fatty acid modification, at resolutions of 3.5 and 3.8 angstroms, respectively. The structure of PTCH1 has internal 2-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and 2 homologous extracellular domains, resembling the architecture of Niemann-Pick C1 protein (NPC1; <a href="/entry/607623">607623</a>). The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N coreceptors. <a href="#37" class="mim-tip-reference" title="Qi, X., Schmiege, P., Coutavas, E., Wang, J., Li, X. <strong>Structures of human Patched and its complex with native palmitoylated sonic hedgehog.</strong> Nature 560: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29995851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29995851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29995851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0308-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29995851">Qi et al. (2018)</a> noted that their biochemical assays showed that SHH-N may use another interface, one that is required for its coreceptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29995851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1:1 PTCH1-HH complex structure reported by <a href="#37" class="mim-tip-reference" title="Qi, X., Schmiege, P., Coutavas, E., Wang, J., Li, X. <strong>Structures of human Patched and its complex with native palmitoylated sonic hedgehog.</strong> Nature 560: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29995851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29995851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29995851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0308-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29995851">Qi et al. (2018)</a> visualized a palmitate-mediated binding site on Hedgehog (HH), which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH coreceptors. <a href="#36" class="mim-tip-reference" title="Qi, X., Schmiege, P., Coutavas, E., Li, X. <strong>Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex.</strong> Science 362: eaas8843, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30139912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30139912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30139912[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aas8843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30139912">Qi et al. (2018)</a> reported a 3.5-angstrom resolution cryoelectron microscopy structure of SHH-N in complex with PTCH1 at a physiologic calcium concentration that reconciled these disparate findings and demonstrated that 1 SHH-N molecule engages both epitopes to bind 2 PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupted the individual interfaces illustrated that simultaneous engagement of both interfaces is required for efficient signaling in cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29995851+30139912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, E. H., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., Scott, M. P. <strong>Human homolog of Patched, a candidate gene for the basal cell nevus syndrome.</strong> Science 272: 1668-1671, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8658145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8658145</a>] [<a href="https://doi.org/10.1126/science.272.5268.1668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8658145">Johnson et al. (1996)</a> mapped the PTC gene to chromosome 9q22.3 by radiation hybrid analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8658145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mapping data of <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> placed the PTC gene between FACC (<a href="/entry/227645">227645</a>) and the marker D9S287 on 9q22.3. The physical map distance between FACC and PTC is less than 650 kb, and the map distance between PTC and D9S287 is less than 290 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Chidambaram, A., Hahn, H., Allikmets, R., Bale, A. E., Dean, M. <strong>The murine homolog (Ptc) of the Drosophila segment polarity gene Patched and the human NBCCS locus maps to mouse chromosome 13. (Abstract)</strong> Am. J. Hum. Genet. 59: A300 only, 1996."None>Chidambaram et al. (1996)</a> used the Jackson Laboratory Backcross DNA panel map service to map the mouse Ptc gene to chromosome 13. Ptc maps close to the murine Facc locus (0 recombinants in 188 meioses). They noted that mouse mutations such as flexed tail (f), purkinje cell degeneration (pcd), and mesenchymal dysplasia (mes), which involve abnormal development of skeletal and neural tissues, are also located in this region of chromosome 13 and may be allelic to Ptc.</p>
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<p>In a father and daughter with Schilbach-Rott syndrome (SBRS; <a href="/entry/164220">164220</a>), <a href="#35" class="mim-tip-reference" title="Prontera, P., Rogaia, D., Sallicandro, E., Mencarelli, A., Imperatore, V., Squeo, G. M., Merla, G., Elisei, S., Moretti-Ferreira, D., Esposito, S., Stangoni, G. <strong>Schilbach-Rott syndrome associated with 9q22.32q22.33 duplication, involving the PTCH1 gene.</strong> Europ. J. Hum. Genet. 27: 1260-1266, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30936464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30936464</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30936464[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/s41431-019-0385-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30936464">Prontera et al. (2019)</a> performed array CGH and identified heterozygosity for a 1.2-Mb duplication of chromosome 9q22.32-q22.33 [arr 9q22.32(98,049,611_98,049,636)x3, 9q22.33(99,301,483_99,301,508)x3; GRCh37] in both affected individuals. The duplication involved 8 genes, including PTCH1. Quantitative PCR analysis of the healthy paternal grandparents did not show the microduplication. The authors suggested that this condition belongs to the holoprosencephaly microform subgroup. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30936464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Basal Cell Nevus Syndrome 1</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, E. H., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., Scott, M. P. <strong>Human homolog of Patched, a candidate gene for the basal cell nevus syndrome.</strong> Science 272: 1668-1671, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8658145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8658145</a>] [<a href="https://doi.org/10.1126/science.272.5268.1668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8658145">Johnson et al. (1996)</a> identified 2 mutations in the PTC coding sequence (<a href="#0001">601309.0001</a> and <a href="/entry/610309#0002">610309.0002</a>) that were associated with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), also called Gorlin syndrome. They also examined the DNA of 12 sporadic basal cell carcinomas (BCCs; see <a href="/entry/605462">605462</a>) and found a point mutation that resulted in a leu175-to-phe amino acid substitution in the predicted first extracellular loop of the protein. Leucine-175 is in exon 3 and is conserved in all reported ptc sequences of mouse, Drosophila, and chicken. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8658145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> used exon sequence and SSCP to search for mutations in the PTC gene in patients with nevoid basal cell carcinoma syndrome (NBCCS). They identified 4 different heterozygous germline mutations (<a href="#0003">601309.0003</a>-<a href="#0006">601309.0006</a>) in unrelated familial cases of NBCCS. They also identified 2 germline mutations in sporadic cases of NBCCS (<a href="#0007">601309.0007</a>-<a href="#0008">601309.0008</a>). In addition, they identified 2 somatic mutations in tumor DNA derived from basal cell carcinomas. Both of these carcinomas had allelic loss of the 9q22.3 NBCCS region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SSCP to screen human 'Patched' in 37 sporadic BCCs in humans, <a href="#16" class="mim-tip-reference" title="Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., Toftgard, R. <strong>The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas.</strong> Nature Genet. 14: 78-81, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782823</a>] [<a href="https://doi.org/10.1038/ng0996-78" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782823">Gailani et al. (1996)</a> detected mutations in one third of the tumors. Direct sequencing of 2 BCCs without SSCP variants revealed mutations in those tumors as well, suggesting to the investigators that inactivation of 'Patched' is probably a necessary step in BCC development. By Northern blot analysis and RNA in situ hybridization, <a href="#16" class="mim-tip-reference" title="Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., Toftgard, R. <strong>The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas.</strong> Nature Genet. 14: 78-81, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782823</a>] [<a href="https://doi.org/10.1038/ng0996-78" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782823">Gailani et al. (1996)</a> showed that 'Patched' is expressed at high levels in tumor cells but not normal skin, suggesting that mutational inactivation of the gene leads to overexpression of mutant transcript owing to failure of a negative feedback mechanism. Nine tumors with loss of heterozygosity (LOH) had mutations of the remaining allele and 2 tumors without LOH had 2 inactivating mutations. Basal cell carcinoma is the most common cancer in humans. Epidemiologic studies had shown a correlation between exposure to sunlight and BCCs, but the association is less striking than that of squamous cell carcinoma of the skin and sunlight. In 15 of the 16 mutations identified in this study, the tumors were from sun-exposed sites. Seven mutations were typical of ultraviolet-B damage: C-T substitutions at dipyrimidine sites, including 2 CC-to-TT double-base mutations. <a href="#16" class="mim-tip-reference" title="Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., Toftgard, R. <strong>The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas.</strong> Nature Genet. 14: 78-81, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782823</a>] [<a href="https://doi.org/10.1038/ng0996-78" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782823">Gailani et al. (1996)</a> noted that the other 8 mutations, including deletions, transversion point mutations, and double-base substitutions other than CC-to-TT, can be caused by ultraviolet-B but are not UVB-specific. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wicking, C., Shanley, S., Smyth, I., Gillies, S., Negus, K., Graham, S., Suthers, G., Haites, N., Edwards, M., Wainwright, B., Chenevix-Trench, G. <strong>Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.</strong> Am. J. Hum. Genet. 60: 21-26, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981943</a>]" pmid="8981943">Wicking et al. (1997)</a> screened 71 unrelated individuals with NBCCS for mutations in the PTCH exons. They identified 28 mutations that were distributed throughout the entire gene and predicted that 86% would cause protein truncation. <a href="#51" class="mim-tip-reference" title="Wicking, C., Shanley, S., Smyth, I., Gillies, S., Negus, K., Graham, S., Suthers, G., Haites, N., Edwards, M., Wainwright, B., Chenevix-Trench, G. <strong>Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.</strong> Am. J. Hum. Genet. 60: 21-26, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981943</a>]" pmid="8981943">Wicking et al. (1997)</a> identified 3 families bearing identical genotypes with variable phenotypes. From this they concluded that phenotypic variability in NBCCS is a complex genetic event. No phenotype/genotype correlation between the position of the truncation mutations and major clinical features was evident. <a href="#51" class="mim-tip-reference" title="Wicking, C., Shanley, S., Smyth, I., Gillies, S., Negus, K., Graham, S., Suthers, G., Haites, N., Edwards, M., Wainwright, B., Chenevix-Trench, G. <strong>Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.</strong> Am. J. Hum. Genet. 60: 21-26, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981943</a>]" pmid="8981943">Wicking et al. (1997)</a> concluded that the preponderance of truncation mutations in the germline of NBCCS patients suggests that the developmental defects associated with NBCCS are likely due to haploinsufficiency. They noted that studies in Drosophila indicate that developmental pathways are particularly sensitive to dosage effects, with absolute levels of certain proteins being critical to the correct functioning of such pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Bale, A. E. <strong>Variable expressivity of Patched mutations in flies and humans. (Editorial)</strong> Am. J. Hum. Genet. 60: 10-12, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981940</a>]" pmid="8981940">Bale (1997)</a> reviewed factors contributing to the variable expressivity of PTCH mutations in NBCCS. He reported that clinical features of NBCCS syndrome differ more among families than between families. <a href="#41" class="mim-tip-reference" title="Shimkets, R., Gailani, M. R., Siu, V. M., Yang-Feng, T., Pressman, C. L., Levanat, S., Goldstein, A., Dean, M., Bale, A. E. <strong>Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients.</strong> Am. J. Hum. Genet. 59: 417-422, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755929</a>]" pmid="8755929">Shimkets et al. (1996)</a> reported 2 patients with small interstitial deletions on chromosome 9q which involved the PTCH gene. Phenotypes of the 2 patients differed with respect to several key findings (e.g., occurrence of jaw cysts, palmar pits, and skeletal abnormalities). <a href="#3" class="mim-tip-reference" title="Bale, A. E. <strong>Variable expressivity of Patched mutations in flies and humans. (Editorial)</strong> Am. J. Hum. Genet. 60: 10-12, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981940</a>]" pmid="8981940">Bale (1997)</a> noted that developmental defects may also arise through a 2-hit mechanism and he reviewed evidence for loss of the normal allele in epithelial cells lining jaw cysts. <a href="#3" class="mim-tip-reference" title="Bale, A. E. <strong>Variable expressivity of Patched mutations in flies and humans. (Editorial)</strong> Am. J. Hum. Genet. 60: 10-12, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981940</a>]" pmid="8981940">Bale (1997)</a> noted the absence of genotype/phenotype correlation in NBCCS and concluded that modifying genes and germline variants resulting in hypomorphic or hypermorphic alleles may play an important role in determining the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8755929+8981940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Approximately 5% of patients with Gorlin syndrome develop medulloblastoma in the first few years of life, and 10% of patients with medulloblastoma diagnosed at age 2 years or under have Gorlin syndrome. <a href="#12" class="mim-tip-reference" title="Cowan, R., Hoban, P., Kelsey, A., Birch, J. M., Gattamaneni, R., Evans, D. G. R. <strong>The gene for the naevoid basal cell carcinoma syndrome acts as a tumor-suppressor gene in medulloblastoma.</strong> Brit. J. Cancer 76: 141-145, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9231911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9231911</a>] [<a href="https://doi.org/10.1038/bjc.1997.354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9231911">Cowan et al. (1997)</a> found that 1 out of 3 unrelated patients with medulloblastoma complicated by Gorlin syndrome had lost the wildtype allele on 9q, indicating that the Gorlin locus probably acts as a tumor suppressor in the development of this tumor. They also confirmed this role in a basal cell carcinoma from the same individual. They suggested that Gorlin syndrome is more common than previously recognized and may not be diagnosed on clinical grounds alone even in middle life. In their Table 1 they provided diagnostic criteria for Gorlin syndrome. Five major and 6 minor criteria were listed. A positive diagnosis can be made, they suggested, on the basis of 2 major or 1 major and 2 minor criteria. Major criteria included multiple (more than 2) BCCs or 1 before age 30 years, or more than 10 basal cell nevi; any odontogenic keratocyst or polyostotic bone cyst; palmar and plantar pits; ectopic calcification; and a family history of NBCCS. Minor criteria included rib or vertebral anomalies; large head circumference with frontal bossing; cardiac or ovarian fibroma; and lymphomesenteric cysts. Falx calcification under the age of 20 years and palmar or plantar pits were among the major criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9231911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Studying patients who presented with multiple odontogenic keratocysts, <a href="#24" class="mim-tip-reference" title="Lench, N. J., Telford, E. A. R., High, A. S., Markham, A. F., Wicking, C., Wainwright, B. J. <strong>Characterisation of human Patched germ line mutations in naevoid basal cell carcinoma syndrome.</strong> Hum. Genet. 100: 497-502, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341860</a>] [<a href="https://doi.org/10.1007/s004390050541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341860">Lench et al. (1997)</a> identified 5 novel germline mutations in PTCH. Four mutations caused premature stop codons and 1 resulted in an amino acid substitution toward the C terminus of the predicted protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Wicking, C., Gillies, S., Smyth, I., Shanley, S., Fowles, L., Ratcliffe, J., Wainwright, B., Chenevix-Trench, G. <strong>De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.</strong> Am. J. Med. Genet. 73: 304-307, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9415689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9415689</a>]" pmid="9415689">Wicking et al. (1997)</a> presented an additional 4 novel PTCH mutations in nevoid basal cell carcinoma syndrome, having previously reported 28 mutations. They identified 8 individuals who carried a de novo mutation in the PTCH gene. In 5 of these cases, clinical and radiologic examination had not unequivocally ruled out a diagnosis in one of the parents. On the basis of the findings in the parents, <a href="#50" class="mim-tip-reference" title="Wicking, C., Gillies, S., Smyth, I., Shanley, S., Fowles, L., Ratcliffe, J., Wainwright, B., Chenevix-Trench, G. <strong>De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.</strong> Am. J. Med. Genet. 73: 304-307, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9415689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9415689</a>]" pmid="9415689">Wicking et al. (1997)</a> presented the following review of diagnostic criteria for this syndrome: (1) although palmar and plantar pitting is pathognomonic of NBCCS, it can be falsely reported; (2) a caution must be exercised in using 'multiple BCC' as a diagnostic criterion, especially in areas of high sun exposure; (3) high-arched palate, a minor diagnostic anomaly, is quite common in the general population; and (4) a dense calcification of the falx was not found in these parents, but is an almost invariable finding in adults with mutations in the PTCH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9415689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aszterbaum, M., Rothman, A., Johnson, R. L., Fisher, M., Xie, J., Bonifas, J. M., Zhang, X., Scott, M. P., Epstein, E. H., Jr. <strong>Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.</strong> J. Invest. Derm. 110: 885-888, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620294</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00222.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620294">Aszterbaum et al. (1998)</a> screened the 23 exons of the PTCH gene for mutations by use of single-strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and 7 basal cell nevus syndrome-associated basal cell carcinomas. This screen identified mutations located in 8 exons in 13 of the basal cell nevus syndrome patients and in 3 of the tumors. The most common mutations were frameshifts resulting in premature chain termination. Of 26 sporadic basal cell carcinomas screened, 11 showed loss of heterozygosity at 1 or more of the polymorphic markers examined in the PTCH gene region. Of these 11, 3 tumors were found to have PTCH gene mutations, each in a different exon of the gene. One of these was predicted to result in an amino acid substitution, 1 in a premature stop codon, and 1 in a frameshift. The latter 2 mutations caused premature chain termination. These 3 mutations were not those considered to be characteristic of UV-induced changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bodak, N., Queille, S., Avril, M. F., Bouadjar, B., Drougard, C., Sarasin, A., Daya-Grosjean, L. <strong>High levels of Patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.</strong> Proc. Nat. Acad. Sci. 96: 5117-5122, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220428</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220428[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.96.9.5117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220428">Bodak et al. (1999)</a> analyzed the PTCH gene, which had been postulated to be a tumor suppressor gene, in 22 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP; see <a href="/entry/278700">278700</a>). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. The data confirmed the presence of high levels of UV-induced mutations (C-to-T or CC-to-TT transitions), all located at the bipyrimidine sites in the PTCH gene. Moreover, in 7 of 14 (50%) BCCs from patients with XP, both PTCH and p53 (<a href="/entry/191170">191170</a>) were mutated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220428" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Matt, D., Xin, H., Vortmeyer, A. O., Zhuang, Z., Burg, G., Boni, R. <strong>Sporadic trichoepithelioma demonstrates deletions at 9q22.3.</strong> Arch. Derm. 136: 657-660, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10815860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10815860</a>] [<a href="https://doi.org/10.1001/archderm.136.5.657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10815860">Matt et al. (2000)</a> studied 29 randomly selected cases of sporadic trichoepithelioma (see <a href="/entry/601606">601606</a>) by microdissection and PCR using paraffin-embedded, formalin-fixed tissue specimens on glass slides. Analysis was performed with the polymorphic markers IFNA and D9S171 (9p21) as well as D9S15, D9S303, D9S287, and D9S252 (9q22.3). Loss of heterozygosity (LOH) at 9q22.3 including the Patched gene was identified in 14 (48%) of 29 cases with at least 1 marker, but could not be demonstrated in any case using the markers IFNA or D9S171 (9p21). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10815860" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Strange, R. C., El-Genidy, N., Ramachandran, S., Lovatt, T. J., Fryer, A. A., Smith, A. G., Lear, J. T., Wong, C., Jones, P. W., Ichii-Jones, F., Hoban, P. R. <strong>Susceptibility to basal cell carcinoma: associations with PTCH polymorphisms.</strong> Ann. Hum. Genet. 68: 536-545, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15598212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15598212</a>] [<a href="https://doi.org/10.1046/j.1529-8817.2004.00132.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15598212">Strange et al. (2004)</a> presented evidence that polymorphisms in the PTCH gene are associated with susceptibility to BCC. They concluded that the association was not mediated by the extent of exposure to ultraviolet radiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15598212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Lindstrom, E., Shimokawa, T., Toftgard, R., Zaphiropoulos, P. G. <strong>PTCH mutations: distribution and analyses.</strong> Hum. Mutat. 27: 215-219, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16419085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16419085</a>] [<a href="https://doi.org/10.1002/humu.20296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16419085">Lindstrom et al. (2006)</a> analyzed the distribution of mutations in the PTCH1 gene underlying the nevoid basal cell carcinoma syndrome and in many different sporadic tumors in which PTCH1 appears to act as a tumor suppressor gene. Sporadic medulloblastomas were among the more frequent of the latter group. Among a group of 152 sporadic tumors, the number of sporadic medulloblastoma mutations was relatively small (23), with 65% nonsense, 22% missense, and 13% putative splice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16419085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#47" class="mim-tip-reference" title="Takahashi, C., Kanazawa, N., Yoshikawa, Y., Yoshikawa, R., Saitoh, Y., Chiyo, H., Tanizawa, T., Hashimoto-Tamaoki, T., Nakano, Y. <strong>Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients.</strong> J. Hum. Genet. 54: 403-408, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557015</a>] [<a href="https://doi.org/10.1038/jhg.2009.55" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19557015">Takahashi et al. (2009)</a> identified 6 different heterozygous truncating germline mutations in the PTCH1 gene in 6 Japanese families with BCNS1. There was no evidence of a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 genomic DNA extracted from the blood of a 21-year-old Japanese woman with palmoplantar pits and multiple jaw cysts, <a href="#33" class="mim-tip-reference" title="Nakamura, M., Tokura, Y. <strong>A novel missense mutation in the PTCH1 gene in a premature case of nevoid basal cell carcinoma syndrome.</strong> Europ. J. Derm. 19: 262-263, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213655</a>] [<a href="https://doi.org/10.1684/ejd.2009.0627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213655">Nakamura and Tokura (2009)</a> directly sequenced the PTCH1 gene and identified heterozygosity for a missense mutation (V442E; <a href="#0018">601309.0018</a>). Her unaffected parents and an affected brother and sister did not participate in the study. The mutation was not found in the Japanese SNP database. The authors noted that although Japan is a genetically closed island, no founder effect had been observed among Japanese NBCCS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Holoprosencephaly 7</em></strong></p><p>
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Holoprosencephaly-3 (HPE3; <a href="/entry/142945">142945</a>) is caused by haploinsufficiency for the Sonic hedgehog gene (SHH; <a href="/entry/600725">600725</a>). <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> hypothesized that mutations in genes encoding components of the SHH signaling pathway also could be associated with holoprosencephaly. PTCH, the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> identified 4 different mutations in PTCH (<a href="#0011">601309.0011</a>-<a href="#0014">601309.0014</a>) in 5 unrelated affected individuals with holoprosencephaly-7 (HPE7; <a href="/entry/610828">610828</a>). They predicted that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations caused decreased SHH signaling, with resulting HPE. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. The findings demonstrated further genetic heterogeneity associated with the HPE phenotype, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Ribeiro, L. A., Murray, J. C., Richieri-Costa, A. <strong>PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.</strong> Am. J. Med. Genet. 140A: 2584-2586, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001668</a>] [<a href="https://doi.org/10.1002/ajmg.a.31369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17001668">Ribeiro et al. (2006)</a> identified 4 different mutations (see, e.g., <a href="#0015">601309.0015</a>) in 5 Brazilian probands, 4 with HPE and 1 with HPE-like facial features with normal MRI. One of the patients reported by <a href="#39" class="mim-tip-reference" title="Ribeiro, L. A., Murray, J. C., Richieri-Costa, A. <strong>PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.</strong> Am. J. Med. Genet. 140A: 2584-2586, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001668</a>] [<a href="https://doi.org/10.1002/ajmg.a.31369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17001668">Ribeiro et al. (2006)</a> was described by <a href="#20" class="mim-tip-reference" title="Guion-Almeida, M. L., Zechi-Ceide, R. M., Richieri-Costa, A. <strong>Cerebro-oculo-nasal syndrome: 13 new Brazilian cases.</strong> Am. J. Med. Genet. 143A: 3252-3266, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17985375</a>] [<a href="https://doi.org/10.1002/ajmg.a.32090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17985375">Guion-Almeida et al. (2007)</a> as having cerebrooculonasal syndrome (CONS; <a href="/entry/605627">605627</a>) (see <a href="#0015">601309.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17985375+17001668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5-year-old Brazilian girl with holoprosencephaly-like phenotype (<a href="/entry/610828">610828</a>), <a href="#38" class="mim-tip-reference" title="Rahimov, F., Ribeiro, L. A., de Miranda, E., Richieri-Costa, A., Murray, J. C. <strong>GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum?</strong> Am. J. Med. Genet. 140A: 2571-2576, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17096318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17096318</a>] [<a href="https://doi.org/10.1002/ajmg.a.31370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17096318">Rahimov et al. (2006)</a> identified double heterozygosity for a mutation in the PTCH1 gene (<a href="#0012">601309.0012</a>) and a mutation in the GLI2 gene (<a href="/entry/165230#0003">165230.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17096318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Derwinska, K., Smyk, M., Cooper, M. L., Bader, P., Cheung, S. W., Stankiewicz, P. <strong>PTCH1 duplication in a family with microcephaly and mild developmental delay.</strong> Europ. J. Hum. Genet. 17: 267-271, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18830227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18830227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18830227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18830227">Derwinska et al. (2009)</a> identified a 360-kb duplication encompassing the entire PTCH1 gene in a mother and son with microcephaly, mild developmental delay, and mild dysmorphic features. The mother had 7 previous miscarriages. The authors postulated that a gain of function of PTCH1 may be involved in a holoprosencephaly-like phenotype, which includes microcephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18830227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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In a cohort of 22 patients with ocular developmental anomalies (ODA), <a href="#7" class="mim-tip-reference" title="Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P. <strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong> Genome Res. 26: 474-485, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26893459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26893459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26893459[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/10.1101/gr.196048.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26893459">Chassaing et al. (2016)</a> identified 4 unrelated patients with a heterozygous variant predicted to be deleterious by in silico analysis in the PTCH1 gene. One patient (P5) with microphthalmia, cataract, and sclerocornea had a frameshift deletion (c.4delG, Glu2AsnfsTer9); 1 patient (P20) with bilateral Peters anomaly had a missense mutation (Y1316C); and 2 patients (P8 and P15) with colobomatous microphthalmia, corpus callosum abnormality, and atrial septal defects had missense mutations (T1064M and V1081M, respectively). With the exception of P5, for whom the authors were unable to perform segregation analysis, the mutation was inherited from an asymptomatic parent. Screening for additional mutations in the PTCH1 gene in the remaining patients identified an additional patient (P17) with Axenfeld-Rieger malformation who had a missense mutation (R1297W). In another cohort of 48 patients with ODA, <a href="#7" class="mim-tip-reference" title="Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P. <strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong> Genome Res. 26: 474-485, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26893459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26893459</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26893459[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/10.1101/gr.196048.115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26893459">Chassaing et al. (2016)</a> identified 2 more heterozygous PTCH1 mutations: I899V in a patient (CC10) with bilateral Peters anomaly, and T778P in a patient (CC44) with anophthalmia/microphthalmia and anterior segment dysgenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26893459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#19" class="mim-tip-reference" title="Goodrich, L. V., Milenkovic, L., Higgins, K. M., Scott, M. P. <strong>Altered neural cell fates and medulloblastoma in mouse Patched mutants.</strong> Science 277: 1109-1113, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9262482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9262482</a>] [<a href="https://doi.org/10.1126/science.277.5329.1109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9262482">Goodrich et al. (1997)</a> investigated the function of the ptc gene by inactivating the gene in mice by homologous recombination in ES cells. Mice homozygous for the mutation died during embryogenesis and were found to have open and overgrown neural tubes. Two Sonic hedgehog (Shh) target genes, ptc itself and Gli (<a href="/entry/165220">165220</a>), were derepressed in the ectoderm and mesoderm but not in the endoderm. Shh targets that are, under normal conditions, transcribed ventrally were aberrantly expressed in dorsal and lateral neural tube cells. <a href="#19" class="mim-tip-reference" title="Goodrich, L. V., Milenkovic, L., Higgins, K. M., Scott, M. P. <strong>Altered neural cell fates and medulloblastoma in mouse Patched mutants.</strong> Science 277: 1109-1113, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9262482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9262482</a>] [<a href="https://doi.org/10.1126/science.277.5329.1109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9262482">Goodrich et al. (1997)</a> concluded that ptc is essential for repression of genes that are locally activated by Shh. Mice heterozygous for the ptch mutation were larger than normal, and a subset of them developed hindlimb defects (including extra digits, syndactyly and soft tissue tumors) or cerebellar medulloblastomas, abnormalities also seen in patients with the basal cell nevus syndrome. The authors speculated that their failure to observe basal cell carcinomas in the heterozygous mice may have been because somatic inactivation of the second ptc gene is required as it is in human basal cell carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9262482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Black, G. C. M., Mazerolle, C. J., Wang, Y., Campsall, K. D., Petrin, D., Leonard, B. C., Damji, K. F., Evans, D. G., McLeod, D., Wallace, V. A. <strong>Abnormalities of the vitreoretinal interface caused by dysregulated hedgehog signaling during retinal development.</strong> Hum. Molec. Genet. 12: 3269-3276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570707</a>] [<a href="https://doi.org/10.1093/hmg/ddg356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570707">Black et al. (2003)</a> showed that PtchlacZ +/- mice exhibited vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ +/- mice exhibited abnormal cell cycle regulation, which culminated in photoreceptor dysplasia and Muller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs can cause significant visual loss in the general, especially elderly, population. <a href="#4" class="mim-tip-reference" title="Black, G. C. M., Mazerolle, C. J., Wang, Y., Campsall, K. D., Petrin, D., Leonard, B. C., Damji, K. F., Evans, D. G., McLeod, D., Wallace, V. A. <strong>Abnormalities of the vitreoretinal interface caused by dysregulated hedgehog signaling during retinal development.</strong> Hum. Molec. Genet. 12: 3269-3276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570707</a>] [<a href="https://doi.org/10.1093/hmg/ddg356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570707">Black et al. (2003)</a> hypothesized that alteration of Muller cell Hh signaling may play a role in the pathogenesis of such age-related 'idiopathic' ERMs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14570707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas induced by an activated Ras oncogene (see Hras, <a href="/entry/190020">190020</a>), whereas FVB/N mice are highly susceptible. <a href="#49" class="mim-tip-reference" title="Wakabayashi, Y., Mao, J.-H., Brown, K., Girardi, M., Balmain, A. <strong>Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.</strong> Nature 445: 761-765, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17230190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17230190</a>] [<a href="https://doi.org/10.1038/nature05489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17230190">Wakabayashi et al. (2007)</a> demonstrated that susceptibility to squamous cell carcinoma is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains are resistant to Ras-induced squamous cell carcinomas, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch-B6) or by overexpression of the FVB/N Ptch allele (Ptch-FVB) in the epidermis of K5Hras-transgenic F1 hybrid mice. The human Patched gene is a classic tumor suppressor gene for all basal cell carcinomas and medulloblastomas, the loss of which causes increased signaling through the SHH pathway. Squamous cell carcinomas that develop in Ptch-B6 heterozygous mice do not lose the wildtype Ptch gene or show evidence of increased SHH signaling. Although Ptch-FVB overexpression can promote squamous cell carcinoma formation, continued expression is not required for tumor maintenance, suggesting a role at an early stage of tumor cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis and binding to Tid1 (<a href="/entry/608382">608382</a>), the mouse homolog of the Drosophila l(2)tid tumor suppressor gene. <a href="#49" class="mim-tip-reference" title="Wakabayashi, Y., Mao, J.-H., Brown, K., Girardi, M., Balmain, A. <strong>Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.</strong> Nature 445: 761-765, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17230190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17230190</a>] [<a href="https://doi.org/10.1038/nature05489" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17230190">Wakabayashi et al. (2007)</a> proposed that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumor types can arise from the same target cell depending on carcinogen exposure and host genetic background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17230190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ohba, S., Kawaguchi, H., Kugimiya, F., Ogasawara, T., Kawamura, N., Saito, T., Ikeda, T., Fujii, K., Miyajima, T., Kuramochi, A., Miyashita, T., Oda, H., Nakamura, K., Takato, T., Chung, U. <strong>Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.</strong> Dev. Cell 14: 689-699, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18477452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18477452</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18477452">Ohba et al. (2008)</a> found that adult Ptch1 +/- mice had higher bone mass than adult wildtype mice. In culture, Ptch1 +/- cells showed accelerated osteoblast differentiation, enhanced responsiveness to Runx2 (<a href="/entry/600211">600211</a>), and reduced generation of the repressor form of Gli3 (<a href="/entry/165240">165240</a>). Administration of a hedgehog signaling inhibitor decreased bone mass in adult wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18477452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 49-year-old man with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#23" class="mim-tip-reference" title="Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, E. H., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., Scott, M. P. <strong>Human homolog of Patched, a candidate gene for the basal cell nevus syndrome.</strong> Science 272: 1668-1671, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8658145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8658145</a>] [<a href="https://doi.org/10.1126/science.272.5268.1668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8658145">Johnson et al. (1996)</a> identified a 9-bp insertion (CCGAATATC) in the PTCH gene. The heterozygous mutation results in the insertion of proline, asparagine, and isoleucine after codon 815 in exon 15 of the gene and is a tandem duplication of 3 amino acids of the normal polypeptide. The patient's affected sister and daughter had the same alteration, but 3 unaffected relatives did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8658145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 18-year-old woman with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#23" class="mim-tip-reference" title="Johnson, R. L., Rothman, A. L., Xie, J., Goodrich, L. V., Bare, J. W., Bonifas, J. M., Quinn, E. H., Myers, R. M., Cox, D. R., Epstein, E. H., Jr., Scott, M. P. <strong>Human homolog of Patched, a candidate gene for the basal cell nevus syndrome.</strong> Science 272: 1668-1671, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8658145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8658145</a>] [<a href="https://doi.org/10.1126/science.272.5268.1668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8658145">Johnson et al. (1996)</a> identified an 11-bp deletion in exon 15 of the PTCH gene. The deletion removes nucleotides 2442 to 2452 from the coding sequence, resulting in an ORF with 9 C-terminal missense codons and a stop signal at codon 823. The patient developed BCC at age 6 years and jaw cysts at age 8. The patient was heterozygous for this mutation and was the first affected member of this family, since her parents had neither BCCs nor other signs of BCNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8658145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267606984 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606984;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=rs267606984" 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=rs267606984" 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=RCV000144436 OR RCV004576922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144436, RCV004576922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144436...</a>
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous C-to-T transition (1081C-T) in the codon for gln210 of PTCH which led to a premature stop codon in exon 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2118419579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2118419579;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=rs2118419579" 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=rs2118419579" 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=RCV004576890" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576890" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576890</a>
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous 37-bp deletion (808_840del) in exon 6 of the PTCH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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PTCH1, 1148G-A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2118365442 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2118365442;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=rs2118365442" 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=rs2118365442" 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=RCV000008698 OR RCV004576891" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008698, RCV004576891" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008698...</a>
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous G-to-A transition (1148G-A) in exon 8 of the PTCH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span class="mim-font">
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<strong>.0006 BASAL CELL NEVUS SYNDROME 1</strong>
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PTCH1, 2-BP INS, 2047CT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2118041703 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2118041703;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=rs2118041703" 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=rs2118041703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004576892" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576892" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576892</a>
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous 2-bp insertion at nucleotide 2047 (2047insCT) in exon 13 of the PTCH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BASAL CELL NEVUS SYNDROME 1</strong>
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PTCH1, 1-BP INS, 2000C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554695110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554695110;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=rs1554695110" 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=rs1554695110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000277549 OR RCV001804162 OR RCV004576942" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000277549, RCV001804162, RCV004576942" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000277549...</a>
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<p>In a patient with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous 1-bp insertion (2000insC) in exon 13 of the PTCH gene, resulting in a premature stop 9 amino acids downstream. The parents did not have the mutation and were free of phenotypic features of BCNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2136689212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2136689212;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=rs2136689212" 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=rs2136689212" 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=RCV004576893" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004576893" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004576893</a>
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<p>In a patient with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#21" class="mim-tip-reference" title="Hahn, H., Wicking, C., Zaphiropoulos, P. G., Gailani, M. R., Shanley, S., Chidambaram, A., Vorechovsky, I., Holmberg, E., Unden, A. B., Gillies, S., Negus, K., Smyth, I., Pressman, C., Leffell, D. J., Gerrard, B., Goldstein, A. M., Dean, M., Toftgard, R., Chenevix-Trench, G., Wainwright, B., Bale, A. E. <strong>Mutations of the human homolog of Drosophila Patched in the nevoid basal cell carcinoma syndrome.</strong> Cell 85: 841-851, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8681379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8681379</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81268-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8681379">Hahn et al. (1996)</a> identified a heterozygous 1-bp deletion (2583delC) in exon 15 of the PTCH gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8681379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 BASAL CELL CARCINOMA, SOMATIC</strong>
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PTCH1, 451C-T, PRO-SER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008702" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008702" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008702</a>
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<p>In the DNA from a somatic basal cell carcinoma (see <a href="/entry/605462">605462</a>) from the cheek, <a href="#16" class="mim-tip-reference" title="Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., Toftgard, R. <strong>The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas.</strong> Nature Genet. 14: 78-81, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782823</a>] [<a href="https://doi.org/10.1038/ng0996-78" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782823">Gailani et al. (1996)</a> found a 451C-T transition in exon 3 of the PTCH1 gene, predicted to result in a pro-to-ser amino acid substitution. LOH in chromosome 9 was also demonstrated. This was 1 of 12 mutations detected by <a href="#16" class="mim-tip-reference" title="Gailani, M. R., Stahle-Backdahl, M., Leffell, D. J., Glynn, M., Zaphiropoulos, P. G., Pressman, C., Unden, A. B., Dean, M., Brash, D. E., Bale, A. E., Toftgard, R. <strong>The role of the human homologue of Drosophila Patched in sporadic basal cell carcinomas.</strong> Nature Genet. 14: 78-81, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782823</a>] [<a href="https://doi.org/10.1038/ng0996-78" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782823">Gailani et al. (1996)</a> in 37 sporadic BCCs studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 BASAL CELL CARCINOMA, SOMATIC</strong>
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PTCH1, 3340A-T, ARG-TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776689 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776689;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=rs587776689" 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=rs587776689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008703" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008703" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008703</a>
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<p>Of the 3 somatic basal cell carcinomas (see <a href="/entry/605462">605462</a>) in which <a href="#1" class="mim-tip-reference" title="Aszterbaum, M., Rothman, A., Johnson, R. L., Fisher, M., Xie, J., Bonifas, J. M., Zhang, X., Scott, M. P., Epstein, E. H., Jr. <strong>Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.</strong> J. Invest. Derm. 110: 885-888, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9620294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9620294</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00222.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9620294">Aszterbaum et al. (1998)</a> found a PTCH mutation, one had a heterozygous 3340A-T transversion in exon 10, predicted to result in an arg-to-trp amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 HOLOPROSENCEPHALY 7</strong>
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PTCH1, ALA393THR
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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> rs199476091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476091;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/rs199476091?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=rs199476091" 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=rs199476091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008704 OR RCV000532256 OR RCV001010144 OR RCV004547466" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008704, RCV000532256, RCV001010144, RCV004547466" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008704...</a>
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<p>In a female with holoprosencephaly (HPE7; <a href="/entry/610828">610828</a>), <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> identified a heterozygous 1165G-A transition in the PTCH gene, resulting in an ala393-to-thr (A393T) substitution in an extracellular loop of the PTCH protein. The variant was also present in her clinically normal father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<strong>.0012 HOLOPROSENCEPHALY 7</strong>
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PTCH1, THR728MET
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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> rs115556836 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs115556836;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/rs115556836?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=rs115556836" 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=rs115556836" 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=RCV000008705 OR RCV000034564 OR RCV000078462 OR RCV000206005 OR RCV000568375 OR RCV002504769" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008705, RCV000034564, RCV000078462, RCV000206005, RCV000568375, RCV002504769" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008705...</a>
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<p>In 2 unrelated probands with holoprosencephaly-7 (HPE7; <a href="/entry/610828">610828</a>), <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> found a 2171C-T transition in the PTCH gene, resulting in a thr728-to-met (T728M) amino acid substitution in an intracellular loop of the PTCH protein. In 1 family, the female proband had semilobar HPE, absence of the corpus callosum, and fusion of the thalami. Her brother had a single central maxillary incisor, bilateral cleft lip/palate, and developmental delay. Their clinically normal mother did not carry the mutation, and their father was not available for testing. In the second family, the female proband had HPE and partial agenesis of the corpus callosum, panhypopituitarism, midline cleft lip and palate, a small omphalocele, and mild to moderate developmental delay. Her phenotypically normal mother did not have the mutation, and the girl's father was not available for testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5-year-old Brazilian girl with a holoprosencephaly-like phenotype, <a href="#38" class="mim-tip-reference" title="Rahimov, F., Ribeiro, L. A., de Miranda, E., Richieri-Costa, A., Murray, J. C. <strong>GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum?</strong> Am. J. Med. Genet. 140A: 2571-2576, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17096318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17096318</a>] [<a href="https://doi.org/10.1002/ajmg.a.31370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17096318">Rahimov et al. (2006)</a> identified double heterozygosity for the T728M mutation and an R151G mutation in the GLI2 gene (<a href="/entry/165230#0003">165230.0003</a>). (The authors erroneously stated that the 2171C-T transition resulted in a T328M substitution.) Clinical features included large ears, hypoplastic anterior nasal spine, diminished frontonasal angle, hypotelorism, hypoplastic premaxilla, hypoplastic nose with flattened alae and nasal tip, poorly developed philtrum, bilateral cleft lip/palate, malocclusion, and normal neuropsychologic development. MRI demonstrated mild gyral asymmetry in the perisylvian areas. The causative nature of the GLI2 mutation was uncertain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17096318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0013" class="mim-anchor"></a>
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<strong>.0013 HOLOPROSENCEPHALY 7</strong>
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PTCH1, SER827GLY
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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> rs199476092 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476092;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/rs199476092?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=rs199476092" 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=rs199476092" 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=RCV000008706 OR RCV000034565 OR RCV000121886 OR RCV000563051 OR RCV001083878 OR RCV004547467" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008706, RCV000034565, RCV000121886, RCV000563051, RCV001083878, RCV004547467" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008706...</a>
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<p>In a female with holoprosencephaly, seizures, and bilateral cleft lip (HPE7; <a href="/entry/610828">610828</a>), <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> found a heterozygous 2467A-G transition in the PTCH gene, resulting in a ser827-to-gly (S827G) substitution in an extracellular loop of the protein. The clinically normal mother also had the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0014" class="mim-anchor"></a>
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<strong>.0014 HOLOPROSENCEPHALY 7</strong>
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PTCH1, THR1052MET
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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> rs138911275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138911275;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/rs138911275?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=rs138911275" 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=rs138911275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008707 OR RCV000034570 OR RCV000121888 OR RCV000148761 OR RCV000574977 OR RCV001081022 OR RCV004547468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008707, RCV000034570, RCV000121888, RCV000148761, RCV000574977, RCV001081022, RCV004547468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008707...</a>
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<p>In a male with alobar holoprosencephaly and hypotelorism and in his brother with hypotelorism and developmental delay (HPE7; <a href="/entry/610828">610828</a>), <a href="#31" class="mim-tip-reference" title="Ming, J. E., Kaupas, M. E., Roessler, E., Brunner, H. G., Golabi, M., Tekin, M., Stratton, R. F., Sujansky, E., Bale, S. J., Muenke, M. <strong>Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.</strong> Hum. Genet. 110: 297-301, 2002. Note: Erratum: Hum. Genet. 111: 464 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941477</a>] [<a href="https://doi.org/10.1007/s00439-002-0695-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941477">Ming et al. (2002)</a> found a heterozygous 3143C-T transition in the PTCH gene resulting in a thr1052-to-met (T1052M) amino acid substitution in an intracellular loop of the PTCH protein. Their clinically normal father also carried the mutation; their sister and mother, both of whom had normal cognitive development, did not carry the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Ribeiro, L. A., Murray, J. C., Richieri-Costa, A. <strong>PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.</strong> Am. J. Med. Genet. 140A: 2584-2586, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001668</a>] [<a href="https://doi.org/10.1002/ajmg.a.31369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17001668">Ribeiro et al. (2006)</a> described the T1052M mutation in a Brazilian girl with holoprosencephaly-like facial features but normal MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17001668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0015" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0015 HOLOPROSENCEPHALY 7</strong>
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PTCH1, VAL908GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199476093 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199476093;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=rs199476093" 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=rs199476093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008708" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008708" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008708</a>
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<span class="mim-text-font">
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<p>In 2 Brazilian female patients with holoprosencephaly-7 (HPE7; <a href="/entry/610828">610828</a>), <a href="#39" class="mim-tip-reference" title="Ribeiro, L. A., Murray, J. C., Richieri-Costa, A. <strong>PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI.</strong> Am. J. Med. Genet. 140A: 2584-2586, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17001668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17001668</a>] [<a href="https://doi.org/10.1002/ajmg.a.31369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17001668">Ribeiro et al. (2006)</a> identified a 2711G-T transversion in exon 17 of the PTCH1 gene, resulting in a val908-to-gly (V908G) substitution in an extracellular domain. The 2 patients differed phenotypically: one had alobar HPE, absent nasal septum, and midline cleft lip-palate, and the other had lobar HPE, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other. The former patient died at 6 months of age. The second patient was reported by <a href="#20" class="mim-tip-reference" title="Guion-Almeida, M. L., Zechi-Ceide, R. M., Richieri-Costa, A. <strong>Cerebro-oculo-nasal syndrome: 13 new Brazilian cases.</strong> Am. J. Med. Genet. 143A: 3252-3266, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17985375</a>] [<a href="https://doi.org/10.1002/ajmg.a.32090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17985375">Guion-Almeida et al. (2007)</a> as having cerebrooculonasal syndrome (<a href="/entry/605627">605627</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17985375+17001668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4>
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<span class="mim-font">
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<strong>.0016 BASAL CELL NEVUS SYNDROME 1</strong>
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PTCH1, 1-BP INS, 1247T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2118336503 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2118336503;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=rs2118336503" 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=rs2118336503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008709 OR RCV004576894" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008709, RCV004576894" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008709...</a>
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<span class="mim-text-font">
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<p>In a 14-year-old Japanese girl with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>) and ulcerative colitis (see <a href="/entry/266600">266600</a>), <a href="#15" class="mim-tip-reference" title="Fujii, K., Miyashita, T., Omata, T., Kobayashi, K., Takanashi, J., Kouchi, K., Yamada, M., Kohno, Y. <strong>Gorlin syndrome with ulcerative colitis in a Japanese girl.</strong> Am. J. Med. Genet. 121A: 65-68, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900905</a>] [<a href="https://doi.org/10.1002/ajmg.a.20082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900905">Fujii et al. (2003)</a> identified a 1-bp insertion (T) at nucleotide 1247 in exon 9 of the PTCH1 gene, resulting in premature termination of the protein. <a href="#34" class="mim-tip-reference" title="Ohba, S., Kawaguchi, H., Kugimiya, F., Ogasawara, T., Kawamura, N., Saito, T., Ikeda, T., Fujii, K., Miyajima, T., Kuramochi, A., Miyashita, T., Oda, H., Nakamura, K., Takato, T., Chung, U. <strong>Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.</strong> Dev. Cell 14: 689-699, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18477452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18477452</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.03.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18477452">Ohba et al. (2008)</a> found that the bone mineral density of the lumbar spine and femoral neck of this patient was elevated compared with an age- and gender-matched control, consistent with their findings in Ptch1 +/- mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12900905+18477452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4>
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<span class="mim-font">
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<strong>.0017 BASAL CELL NEVUS SYNDROME 1</strong>
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PTCH1, TRP129TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1587692888 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1587692888;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=rs1587692888" 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=rs1587692888" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030726 OR RCV004576912" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030726, RCV004576912" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030726...</a>
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<p>In a 12-year-old boy with basal cell nevus syndrome (BCNS1; <a href="/entry/109400">109400</a>), <a href="#44" class="mim-tip-reference" title="Suzuki, M., Hatsuse, H., Nagao, K., Takayama, Y., Kameyama, K., Kabasawa, Y., Omura, K., Yoshida, M., Fujii, K., Miyashita, T. <strong>Selective haploinsufficiency of longer isoforms of PTCH1 protein can cause nevoid basal cell carcinoma syndrome.</strong> J. Hum. Genet. 57: 422-426, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22572734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22572734</a>] [<a href="https://doi.org/10.1038/jhg.2012.45" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22572734">Suzuki et al. (2012)</a> identified a de novo heterozygous 387G-A transition in exon 2 of the PTCH1 gene, resulting in a trp129-to-ter (W129X) substitution. RT-PCR and protein translation studies indicated that the mutant allele was translated from the second initiation codon in exon 3, generating the short PTCH1 isoform, whereas the PTCHM isoform was degraded. The findings indicated that the phenotype resulted from selective haploinsufficiency of PTCHL and PTCHM, but not PTCHS. The patient had palmar and plantar pits, calcification of the falx cerebri, and keratocystic odontogenic tumor. He also had macrocephaly and scoliosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22572734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0018 BASAL CELL NEVUS SYNDROME 1</strong>
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PTCH1, VAL442GLU
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004577311" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004577311" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004577311</a>
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<p>In a 21-year-old Japanese woman with palmoplantar pits and multiple jaw cysts (BCNS1; <a href="/entry/109400">109400</a>), <a href="#33" class="mim-tip-reference" title="Nakamura, M., Tokura, Y. <strong>A novel missense mutation in the PTCH1 gene in a premature case of nevoid basal cell carcinoma syndrome.</strong> Europ. J. Derm. 19: 262-263, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213655</a>] [<a href="https://doi.org/10.1684/ejd.2009.0627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213655">Nakamura and Tokura (2009)</a> directly sequenced the PTCH1 gene and identified heterozygosity for a c.1325T-A transversion in exon 9, resulting in a val442-to-glu (V442E) substitution within the second transmembrane domain. Her unaffected parents and an affected brother and sister did not participate in the study. The mutation was not found in the Japanese SNP database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Black2003" class="mim-anchor"></a>
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Black, G. C. M., Mazerolle, C. J., Wang, Y., Campsall, K. D., Petrin, D., Leonard, B. C., Damji, K. F., Evans, D. G., McLeod, D., Wallace, V. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14570707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg356" target="_blank">Full Text</a>]
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<a id="Bodak1999" class="mim-anchor"></a>
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Bodak, N., Queille, S., Avril, M. F., Bouadjar, B., Drougard, C., Sarasin, A., Daya-Grosjean, L.
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[<a href="https://doi.org/10.1073/pnas.96.9.5117" target="_blank">Full Text</a>]
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<a id="Casali2004" class="mim-anchor"></a>
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Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P.
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de la Roche, M., Ritter, A. T., Angus, K. L., Dinsmore, C., Earnshaw, C. H., Reiter, J. F., Griffiths, G. M.
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Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192414" 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/nature00989" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="47" class="mim-anchor"></a>
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<a id="Takahashi2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Takahashi, C., Kanazawa, N., Yoshikawa, Y., Yoshikawa, R., Saitoh, Y., Chiyo, H., Tanizawa, T., Hashimoto-Tamaoki, T., Nakano, Y.
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<strong>Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients.</strong>
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J. Hum. Genet. 54: 403-408, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19557015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19557015</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19557015" 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/jhg.2009.55" target="_blank">Full Text</a>]
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<a id="48" class="mim-anchor"></a>
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<a id="Thibert2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thibert, C., Teillet, M.-A., Lapointe, F., Mazelin, L., Le Douarin, N. M., Mehlen, P.
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<strong>Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog.</strong>
|
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Science 301: 843-846, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907805</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907805" 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/10.1126/science.1085405" target="_blank">Full Text</a>]
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<li>
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<a id="49" class="mim-anchor"></a>
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<a id="Wakabayashi2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wakabayashi, Y., Mao, J.-H., Brown, K., Girardi, M., Balmain, A.
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<strong>Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.</strong>
|
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Nature 445: 761-765, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17230190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17230190</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17230190" 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/nature05489" target="_blank">Full Text</a>]
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<li>
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<a id="50" class="mim-anchor"></a>
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<a id="Wicking1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wicking, C., Gillies, S., Smyth, I., Shanley, S., Fowles, L., Ratcliffe, J., Wainwright, B., Chenevix-Trench, G.
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<strong>De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.</strong>
|
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Am. J. Med. Genet. 73: 304-307, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9415689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9415689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9415689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="51" class="mim-anchor"></a>
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<a id="Wicking1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wicking, C., Shanley, S., Smyth, I., Gillies, S., Negus, K., Graham, S., Suthers, G., Haites, N., Edwards, M., Wainwright, B., Chenevix-Trench, G.
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<strong>Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.</strong>
|
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Am. J. Hum. Genet. 60: 21-26, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</ol>
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<br />
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</div>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/12/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/19/2022<br>Bao Lige - updated : 08/27/2021<br>Ada Hamosh - updated : 11/26/2018<br>Ada Hamosh - updated : 09/21/2018<br>Ada Hamosh - updated : 4/5/2016<br>Patricia A. Hartz - updated : 4/1/2016<br>Ada Hamosh - updated : 8/6/2014<br>Ada Hamosh - updated : 8/6/2014<br>Ada Hamosh - updated : 1/30/2014<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 1/7/2010<br>Nara Sobreira - updated : 9/9/2009<br>Cassandra L. Kniffin - updated : 8/31/2009<br>Ada Hamosh - updated : 5/12/2009<br>Patricia A. Hartz - updated : 10/9/2008<br>Ada Hamosh - updated : 8/20/2007<br>Ada Hamosh - updated : 6/26/2007<br>Victor A. McKusick - updated : 2/23/2007<br>Victor A. McKusick - updated : 4/28/2006<br>George E. Tiller - updated : 1/10/2006<br>Patricia A. Hartz - updated : 5/4/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 11/10/2004<br>Ada Hamosh - updated : 9/15/2003<br>Ada Hamosh - updated : 9/13/2002<br>Ada Hamosh - updated : 9/10/2002<br>Victor A. McKusick - updated : 5/13/2002<br>George E. Tiller - updated : 6/19/2001<br>Ada Hamosh - updated : 9/1/2000<br>Victor A. McKusick - updated : 2/18/2000<br>Victor A. McKusick - updated : 9/15/1998<br>Victor A. McKusick - updated : 12/30/1997<br>Victor A. McKusick - updated : 10/7/1997<br>Victor A. McKusick - updated : 9/16/1997<br>Victor A. McKusick - updated : 8/27/1997<br>Moyra Smith - updated : 1/24/1997<br>Mark H. Paalman - updated : 12/3/1996<br>Moyra Smith - updated : 11/19/1996<br>Moyra Smith - updated : 11/13/1996<br>Moyra Smith - updated : 7/2/1996
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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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</span>
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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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Moyra Smith : 6/14/1996
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/30/2024
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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 : 06/12/2024<br>carol : 04/24/2023<br>alopez : 01/19/2022<br>carol : 08/30/2021<br>mgross : 08/27/2021<br>carol : 08/23/2019<br>carol : 07/12/2019<br>alopez : 11/26/2018<br>alopez : 09/21/2018<br>carol : 05/19/2018<br>carol : 05/18/2018<br>carol : 05/27/2016<br>alopez : 4/14/2016<br>carol : 4/5/2016<br>carol : 4/4/2016<br>mgross : 4/1/2016<br>carol : 2/5/2016<br>carol : 9/10/2014<br>alopez : 8/6/2014<br>alopez : 8/6/2014<br>alopez : 8/6/2014<br>alopez : 1/30/2014<br>carol : 10/1/2013<br>carol : 9/16/2013<br>carol : 5/29/2013<br>carol : 4/22/2013<br>carol : 9/11/2012<br>ckniffin : 9/11/2012<br>ckniffin : 9/11/2012<br>carol : 10/26/2010<br>wwang : 1/22/2010<br>terry : 1/20/2010<br>ckniffin : 1/7/2010<br>carol : 9/9/2009<br>wwang : 9/9/2009<br>ckniffin : 8/31/2009<br>alopez : 5/13/2009<br>alopez : 5/13/2009<br>terry : 5/12/2009<br>alopez : 3/19/2009<br>mgross : 10/9/2008<br>mgross : 10/9/2008<br>terry : 10/8/2008<br>ckniffin : 6/15/2008<br>carol : 1/15/2008<br>alopez : 8/28/2007<br>terry : 8/20/2007<br>alopez : 7/2/2007<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>wwang : 3/1/2007<br>terry : 2/23/2007<br>alopez : 5/2/2006<br>terry : 4/28/2006<br>wwang : 1/27/2006<br>terry : 1/10/2006<br>carol : 6/9/2005<br>mgross : 5/9/2005<br>terry : 5/4/2005<br>wwang : 3/18/2005<br>terry : 3/15/2005<br>alopez : 1/18/2005<br>terry : 1/14/2005<br>tkritzer : 11/10/2004<br>alopez : 3/17/2004<br>alopez : 9/15/2003<br>alopez : 9/13/2002<br>carol : 9/13/2002<br>alopez : 9/11/2002<br>tkritzer : 9/10/2002<br>tkritzer : 9/10/2002<br>alopez : 5/16/2002<br>alopez : 5/15/2002<br>alopez : 5/15/2002<br>alopez : 5/15/2002<br>terry : 5/13/2002<br>carol : 1/14/2002<br>cwells : 6/20/2001<br>cwells : 6/19/2001<br>alopez : 9/1/2000<br>mgross : 3/16/2000<br>terry : 2/18/2000<br>carol : 9/18/1998<br>terry : 9/15/1998<br>dholmes : 12/30/1997<br>dholmes : 12/30/1997<br>dholmes : 12/30/1997<br>dholmes : 12/30/1997<br>mark : 10/14/1997<br>terry : 10/7/1997<br>mark : 9/22/1997<br>terry : 9/16/1997<br>mark : 8/28/1997<br>terry : 8/27/1997<br>mark : 7/10/1997<br>terry : 1/28/1997<br>terry : 1/28/1997<br>terry : 1/24/1997<br>mark : 1/24/1997<br>terry : 12/5/1996<br>mark : 12/3/1996<br>mark : 11/19/1996<br>mark : 11/14/1996<br>mark : 11/13/1996<br>mark : 11/13/1996<br>randy : 9/3/1996<br>randy : 8/31/1996<br>terry : 8/31/1996<br>joanna : 8/30/1996<br>mark : 8/7/1996<br>mark : 7/2/1996<br>mark : 7/2/1996<br>mark : 7/2/1996<br>mark : 6/24/1996<br>mark : 6/19/1996<br>mark : 6/18/1996<br>terry : 6/17/1996<br>mark : 6/14/1996
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601309
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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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PATCHED 1; PTCH1
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</span>
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</h3>
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<div>
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<br />
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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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<h4>
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<span class="mim-font">
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PATCHED, DROSOPHILA, HOMOLOG OF, 1<br />
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PTCH<br />
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PTC
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</span>
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</h4>
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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: PTCH1</em></strong>
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</span>
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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> 69408002;
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</span>
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</p>
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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>
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<em>
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Cytogenetic location: 9q22.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:95,442,980-95,516,971 </span>
|
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
|
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<span class="mim-font">
|
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9q22.32
|
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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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Basal cell carcinoma, somatic
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
605462
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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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|
Basal cell nevus syndrome 1
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
109400
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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 class="mim-font">
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Holoprosencephaly 7
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</td>
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<span class="mim-font">
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610828
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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</span>
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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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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</h4>
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<p>The Drosophila 'Patched' (ptc) gene encodes a transmembrane protein that represses transcription in specific cells of genes encoding members of the TGF-beta (see 190180) and Wnt (164820) families of signaling proteins. Vertebrate homologs of ptc have been identified in mice, chickens, and zebrafish. Johnson et al. (1996) reported the isolation and mapping of the human homolog of the Drosophila ptc gene. They cloned the human PTC gene by screening a human lung cDNA library with mouse ptc cDNA clones. They assembled 5.1 kb of contiguous sequence containing a 4.5-kb open reading frame that encodes a 1,447-amino acid protein. The predicted amino acid sequence has 96% identity to mouse and a 40% identity to Drosophila ptc proteins. The human PTC protein is predicted to contain 12 hydrophobic membrane-spanning domains and 2 large hydrophilic extracellular loops. </p><p>Hahn et al. (1996) likewise isolated a human sequence with strong homology to the Drosophila segment polarity gene 'Patched' from a YAC and cosmid contig of the nevoid basal cell carcinoma (NBCCS) region on chromosome 9q22.3. </p><p>Using RT-PCR, Nagao et al. (2005) identified 7 human PTCH transcripts that differ through their use of 5 possible first exons and alternative splicing involving 2 of the possible first exons. These mRNAs encode 4 PTCH proteins with different N termini, including one, designated PTCH-S, that is N-terminally truncated and lacks the first transmembrane domain. RT-PCR detected expression of PTCH in all tissues examined, with lowest levels in heart and liver. Expression of individual PTCH transcripts was tissue specific. Nagao et al. (2005) also identified multiple Ptch splice variants in mouse. During mouse embryonic development, expression of Ptch was highest at embryonic day 10.5, and it declined thereafter. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>To assess the role of Ptc in cell physiology and development, Marigo et al. (1996) expressed the chick Patched gene in Xenopus laevis oocytes (oocytes do not express endogenous Ptc). Protein of the size expected for Ptc was detected 48 hours after injection. They then performed binding assays on injected, uninjected, and control-injected oocytes using the N-terminal fragment (N-Shh) of human Sonic hedgehog protein (SHH; 600725). The binding assay showed that labeled N-Shh protein could bind to Ptc-injected oocytes, but not to the control oocytes. Injected oocytes bound human N-Shh produced in E. coli and mouse N-Shh produced in the baculovirus system. Marigo et al. (1996) demonstrated direct interaction between Ptc and Shh using coimmunoprecipitation studies. They also showed that the 2 extracellular loops of the Ptc protein are necessary for binding and that binding also requires that the Ptc protein be glycosylated. Marigo et al. (1996) proposed that Ptc does not carry out signaling to the cell directly but that an additional molecule is involved, namely the 7-transmembrane protein 'Smoothened ' (SMO; 601500). </p><p>Independently and simultaneously, Stone et al. (1996) concluded that the Ptc gene encodes a candidate receptor for Shh by showing that epitope-tagged N-Shh binds specifically to human embryonic kidney 293 cells expressing mouse Ptc. Ptc also could be immunoprecipitated by N-Shh-IgG. The authors calculated a K(d) of 460 picoM for binding of N-Shh and mouse Ptc. By expression of genes in 293 cells with subsequent lysis and immunoprecipitation, Stone et al. (1996) showed that Ptc, Smo, and Shh form a physical complex in vivo and that a Smo-Shh complex does not form in the absence of Ptc. They proposed that the hedgehog system may provide mitogenic or differentiative signals to basal cells in the skin throughout life. They also raised the possibility that BCNS and BCC might result from constitutive activation of Smo which becomes oncogenic after its release from inhibition by Ptc. </p><p>On the basis of their studies in Drosophila, Chen and Struhl (1996) presented evidence that Ptc acts as a receptor for hedgehog (Hh) proteins. They suggested a novel signal transduction mechanism in which Hh proteins bind to Ptc or to a Ptc-Smo complex and thereby induces Smo activity. Their results showed further that Ptc limits the range of Hh action and that the high levels of Ptc induced by Hh serve to sequester any free Hh and thereby create a barrier to its further movement. </p><p>Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and other human tumors are associated with mutations that activate the protooncogene 'Smoothened' or that inactivate the tumor suppressor 'Patched.' Smoothened and Patched mediate the cellular response to the hedgehog secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the hedgehog response pathway. Taipale et al. (2000) showed that the plant-derived teratogen cyclopamine, which inhibits the hedgehog response, is a potential mechanism-based therapeutic agent for treatment of these tumors. Taipale et al. (2000) showed that cyclopamine or synthetic derivatives with improved potency block activation of the hedgehog response pathway and abnormal cell growth associated with both types of oncogenic mutation. Taipale et al. (2000) concluded that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened. </p><p>Bale and Yu (2001) reviewed the hedgehog pathway and its disruption as a basis for basal cell carcinomas. </p><p>Taipale et al. (2002) reported that Ptc and Smo are not significantly associated with hedgehog-responsive cells and that free Ptc (unbound by hedgehog) acts substoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a 12-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters. Taipale et al. (2002) demonstrated that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. Taipale et al. (2002) suggested that the Ptc tumor suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule. </p><p>During early development in vertebrates, SHH is produced by the notochord and the floor plate. A ventrodorsal gradient of SHH directs ventrodorsal patterning of the neural tube. However, SHH is also required for the survival of neuroepithelial cells. Thibert et al. (2003) demonstrated that PTC induces apoptotic cell death unless its ligand SHH is present to block the signal. Moreover, the blockade of Ptc-induced cell death partly rescues the chick spinal cord defect provoked by Shh deprivation. Thibert et al. (2003) concluded that the proapoptotic activity of unbound PTC and the positive effect of SHH-bound PTC on cell differentiation probably cooperate to achieve the appropriate spinal cord development. </p><p>Casali and Struhl (2004) demonstrated that a cell's measure of ambient Hh concentration is not determined solely by the number of active (unliganded) Ptc molecules. Instead, they found that Hh-bound Ptc can titrate the inhibitory action of unbound Ptc. Furthermore, this effect is sufficient to allow normal reading of the Hh gradient in the presence of a form of Ptc that cannot bind the ligand but retains its ability to inhibit Smo. Casali and Struhl (2004) concluded that their results supported a model in which the ratio of bound to unbound Ptc molecules determines the cellular response to Hh. </p><p>Chen et al. (2004) found that 2 molecules interact with mammalian Smo in an activation-dependent manner: G protein-coupled receptor kinase-2 (GRK2; 109635) leads to phosphorylation of Smo, and beta-arrestin-2 (ARRB2; 107941) fused to green fluorescent protein interacts with Smo. These 2 processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits association of Arrb2 with Smo, and this inhibition is relieved in cells treated with Shh (600725). A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by Grk2 and interaction of Arrb2 with Smo. Chen et al. (2004) suggested that Arrb2 and Grk2 are thus potential mediators of signaling by activated Smo. </p><p>Nagao et al. (2005) demonstrated that GLI1 (165220) regulated PTCH expression. GLI1 induced the expression of individual PTCH transcripts in a cell type-specific manner. Nagao et al. (2005) identified several GLI1-binding sites in the PTCH promoter region, and they showed that GLI1 interacted directly with the promoter region by electrophoretic mobility shift assay and chromatin immunoprecipitation. The longer PTCH isoforms, which interacted strongly with GLI1 in vitro, induced apoptosis in transfected human embryonic kidney cells, but the shortest isoform, PTCH-S, did not. Nagao et al. (2005) determined that PTCH-S was much less stable than the longer isoforms. </p><p>Rohatgi et al. (2007) investigated the role of primary cilia in the regulation of PTCH1, the receptor for SHH. In mammalian cells, PTCH1 localized to cilia and inhibited Smoothened (SMO; 601500) by preventing its accumulation within cilia. When SHH bound to PTCH1, PTCH1 left the cilia, leading to accumulation of SMO and activation of signaling. Thus, Rohatgi et al. (2007) concluded that primary cilia sense SHH and transduce signals that play critical roles in development, carcinogenesis, and stem cell function. </p><p>By X-gal staining of Ptch1 +/- mice carrying a LacZ knockin null allele of Ptch1, Mak et al. (2008) found that Ptch1 was expressed in the perichondrium at postnatal day 5, and that expression progressively decreased as osteoblasts became more mature in the cortical and trabecular bone. There was no detectable staining in osteocytes. Ptch1 was also expressed in the calvarial osteoblasts of both postnatal day-5 and 1-year-old Ptch1 +/- mice, and expression was reduced as osteoblasts matured and grew further way from the suture. </p><p>Gao et al. (2009) showed that the E95K mutation in IHH (600726.0001) resulting in brachydactyly type 1 (BDA1; 112500) impairs the interaction of IHH with PTCH1 and HIP1 (HHIP; 606178). This was consistent with the findings of McLellan et al. (2008) showing that IHH mutations resulting in BDA1 cluster in a calcium-binding site essential for the interaction with its receptor and cell surface partners. Furthermore, Gao et al. (2009) showed that in a mouse model that recapitulated the E95K mutation there was a change in the potency and range of signaling. The mice had digital abnormalities consistent with the human disorder. </p><p>Znf431 (619505) directly suppressed Ptch1 basal expression by binding to 3 response elements in the promoter of Ptch1 variant-1b in mouse MPLB cells. Znf431 also repressed the cellular response to Hh signaling by repressing expression of Hh signal components. The Hh signaling response was decreased in Znf431-overexpressing cells, whereas it was elevated in Znf431-knockdown cells.</p><p>In their review, Huang et al. (2012) stated that Znf431, which they called Zfp932, binds to the promoter region of Ptch1 variant-1b through its zinc fingers. Crystallographic studies showed that each zinc finger binds to 3 bp in the DNA sequence and that Zfp932 uses 2 of its 15 zinc fingers when binding to the Ptch1 promoter. </p><p>The centrosome is essential for cytotoxic T lymphocyte function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunologic synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog signaling. Lymphocytes do not form primary cilia, but de la Roche et al. (2013) found that Hedgehog signaling plays an important role in cytotoxic T lymphocyte killing. T cell receptor activation, which 'prearms' cytotoxic T lymphocytes with cytotoxic granules, also initiated Hedgehog signaling through IHH, PTCH1, and SMOH (601500), which are localized on intracellular vesicles that polarize toward the immunologic synapse. Hedgehog pathway activation occurred intracellularly and triggered RAC1 (602048) synthesis. These events 'prearmed' cytotoxic T lymphocytes for action by promoting the actin remodeling required for centrosome polarization and granule release. De la Roche et al. (2013) concluded that Hedgehog signaling plays a role in cytotoxic T lymphocyte function and that the immunologic synapse may represent a modified cilium. </p><p>Cooper et al. (2014) showed that digit loss can occur both during early limb patterning and at later post-patterning stages of chondrogenesis. In the odd-toed jerboa (Dipus sagitta) and horse and the even-toed camel, extensive cell death sculpts the tissue around the remaining toes. In contrast, digit loss in the pig is orchestrated by earlier limb patterning mechanisms, including downregulation of Ptch1 expression, but there is no increase in cell death. Cooper et al. (2014) concluded that these data demonstrated remarkable plasticity in the mechanisms of vertebrate limb evolution and shed light on the complexity of morphologic convergence, particularly within the artiodactyl lineage. </p><p>Lopez-Rios et al. (2014) analyzed bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH; 600725) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded Shh signaling during bovine handplate development. Lopez-Rios et al. (2014) concluded that their study provided a molecular explanation for the loss of digit asymmetry in bovine limb buds, and suggested that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs. </p><p>Using chromatin immunoprecipitation analysis, Chassaing et al. (2016) found that Sox2 (184429) bound to a sequence within intron 15 of the mouse Ptch1 gene. Suppression of sox2 expression in zebrafish upregulated ptch1 expression and resulted in reduced eye and retina size. Knockdown of ptch1 in zebrafish also caused ocular defects, including reduced eye size. Reduced ptch1 protein in zebrafish led to overactive SHH signaling. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hahn et al. (1996) defined the intron-exon boundaries of the PTC gene and reported that the PTC gene contains 23 exons spanning approximately 34 kb. They noted that there are at least 3 different forms of the PTC protein present in mammalian cells; the ancestral form and 2 human forms. The first in-frame methionine codon for one of the forms is in the third exon. The other human form of PTC contains an open reading frame that extends through to the 5-prime end and may be initiated by upstream sequences. Hahn et al. (1996) pointed out that the identification of several potential forms of the PTC protein provides a mechanism whereby a single PTC gene could play a role in different pathways. They stressed that determination of the regulation of different splice forms of PTC mRNA may shed light on the apparent role of the gene in embryonic development and growth control in adult cells. </p><p>Nagao et al. (2005) determined that the PTCH gene contains 5 alternative first exons in addition to the other 22 exons. The PTCH gene covers about 70 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Gong et al. (2018) reported the cryoelectron microscopy structures of human PTCH1 alone and in complex with the N-terminal domain of human Sonic hedgehog (SHH; 600725) at resolutions of 3.9 and 3.6 angstroms, respectively. PTCH1 comprises 2 interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments, with transmembrane segments 2 to 6 constituting the sterol-sensing domain. Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the sterol-sensing domain. Structure-guided mutational analysis showed that interaction between the N terminus of SHH and PTCH1 is steroid-dependent. </p><p>Qi et al. (2018) reported the cryoelectron microscopy structures of human PTCH1 alone and in complex with the N-terminal domain of 'native' SHH (SHH-N), which has both a C-terminal cholesterol and an N-terminal fatty acid modification, at resolutions of 3.5 and 3.8 angstroms, respectively. The structure of PTCH1 has internal 2-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and 2 homologous extracellular domains, resembling the architecture of Niemann-Pick C1 protein (NPC1; 607623). The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N coreceptors. Qi et al. (2018) noted that their biochemical assays showed that SHH-N may use another interface, one that is required for its coreceptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. </p><p>The 1:1 PTCH1-HH complex structure reported by Qi et al. (2018) visualized a palmitate-mediated binding site on Hedgehog (HH), which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH coreceptors. Qi et al. (2018) reported a 3.5-angstrom resolution cryoelectron microscopy structure of SHH-N in complex with PTCH1 at a physiologic calcium concentration that reconciled these disparate findings and demonstrated that 1 SHH-N molecule engages both epitopes to bind 2 PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupted the individual interfaces illustrated that simultaneous engagement of both interfaces is required for efficient signaling in cells. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Johnson et al. (1996) mapped the PTC gene to chromosome 9q22.3 by radiation hybrid analysis. </p><p>The mapping data of Hahn et al. (1996) placed the PTC gene between FACC (227645) and the marker D9S287 on 9q22.3. The physical map distance between FACC and PTC is less than 650 kb, and the map distance between PTC and D9S287 is less than 290 kb. </p><p>Chidambaram et al. (1996) used the Jackson Laboratory Backcross DNA panel map service to map the mouse Ptc gene to chromosome 13. Ptc maps close to the murine Facc locus (0 recombinants in 188 meioses). They noted that mouse mutations such as flexed tail (f), purkinje cell degeneration (pcd), and mesenchymal dysplasia (mes), which involve abnormal development of skeletal and neural tissues, are also located in this region of chromosome 13 and may be allelic to Ptc.</p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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<span class="mim-text-font">
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<p>In a father and daughter with Schilbach-Rott syndrome (SBRS; 164220), Prontera et al. (2019) performed array CGH and identified heterozygosity for a 1.2-Mb duplication of chromosome 9q22.32-q22.33 [arr 9q22.32(98,049,611_98,049,636)x3, 9q22.33(99,301,483_99,301,508)x3; GRCh37] in both affected individuals. The duplication involved 8 genes, including PTCH1. Quantitative PCR analysis of the healthy paternal grandparents did not show the microduplication. The authors suggested that this condition belongs to the holoprosencephaly microform subgroup. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Basal Cell Nevus Syndrome 1</em></strong></p><p>
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Johnson et al. (1996) identified 2 mutations in the PTC coding sequence (601309.0001 and 610309.0002) that were associated with basal cell nevus syndrome (BCNS1; 109400), also called Gorlin syndrome. They also examined the DNA of 12 sporadic basal cell carcinomas (BCCs; see 605462) and found a point mutation that resulted in a leu175-to-phe amino acid substitution in the predicted first extracellular loop of the protein. Leucine-175 is in exon 3 and is conserved in all reported ptc sequences of mouse, Drosophila, and chicken. </p><p>Hahn et al. (1996) used exon sequence and SSCP to search for mutations in the PTC gene in patients with nevoid basal cell carcinoma syndrome (NBCCS). They identified 4 different heterozygous germline mutations (601309.0003-601309.0006) in unrelated familial cases of NBCCS. They also identified 2 germline mutations in sporadic cases of NBCCS (601309.0007-601309.0008). In addition, they identified 2 somatic mutations in tumor DNA derived from basal cell carcinomas. Both of these carcinomas had allelic loss of the 9q22.3 NBCCS region. </p><p>Using SSCP to screen human 'Patched' in 37 sporadic BCCs in humans, Gailani et al. (1996) detected mutations in one third of the tumors. Direct sequencing of 2 BCCs without SSCP variants revealed mutations in those tumors as well, suggesting to the investigators that inactivation of 'Patched' is probably a necessary step in BCC development. By Northern blot analysis and RNA in situ hybridization, Gailani et al. (1996) showed that 'Patched' is expressed at high levels in tumor cells but not normal skin, suggesting that mutational inactivation of the gene leads to overexpression of mutant transcript owing to failure of a negative feedback mechanism. Nine tumors with loss of heterozygosity (LOH) had mutations of the remaining allele and 2 tumors without LOH had 2 inactivating mutations. Basal cell carcinoma is the most common cancer in humans. Epidemiologic studies had shown a correlation between exposure to sunlight and BCCs, but the association is less striking than that of squamous cell carcinoma of the skin and sunlight. In 15 of the 16 mutations identified in this study, the tumors were from sun-exposed sites. Seven mutations were typical of ultraviolet-B damage: C-T substitutions at dipyrimidine sites, including 2 CC-to-TT double-base mutations. Gailani et al. (1996) noted that the other 8 mutations, including deletions, transversion point mutations, and double-base substitutions other than CC-to-TT, can be caused by ultraviolet-B but are not UVB-specific. </p><p>Wicking et al. (1997) screened 71 unrelated individuals with NBCCS for mutations in the PTCH exons. They identified 28 mutations that were distributed throughout the entire gene and predicted that 86% would cause protein truncation. Wicking et al. (1997) identified 3 families bearing identical genotypes with variable phenotypes. From this they concluded that phenotypic variability in NBCCS is a complex genetic event. No phenotype/genotype correlation between the position of the truncation mutations and major clinical features was evident. Wicking et al. (1997) concluded that the preponderance of truncation mutations in the germline of NBCCS patients suggests that the developmental defects associated with NBCCS are likely due to haploinsufficiency. They noted that studies in Drosophila indicate that developmental pathways are particularly sensitive to dosage effects, with absolute levels of certain proteins being critical to the correct functioning of such pathways. </p><p>Bale (1997) reviewed factors contributing to the variable expressivity of PTCH mutations in NBCCS. He reported that clinical features of NBCCS syndrome differ more among families than between families. Shimkets et al. (1996) reported 2 patients with small interstitial deletions on chromosome 9q which involved the PTCH gene. Phenotypes of the 2 patients differed with respect to several key findings (e.g., occurrence of jaw cysts, palmar pits, and skeletal abnormalities). Bale (1997) noted that developmental defects may also arise through a 2-hit mechanism and he reviewed evidence for loss of the normal allele in epithelial cells lining jaw cysts. Bale (1997) noted the absence of genotype/phenotype correlation in NBCCS and concluded that modifying genes and germline variants resulting in hypomorphic or hypermorphic alleles may play an important role in determining the phenotype. </p><p>Approximately 5% of patients with Gorlin syndrome develop medulloblastoma in the first few years of life, and 10% of patients with medulloblastoma diagnosed at age 2 years or under have Gorlin syndrome. Cowan et al. (1997) found that 1 out of 3 unrelated patients with medulloblastoma complicated by Gorlin syndrome had lost the wildtype allele on 9q, indicating that the Gorlin locus probably acts as a tumor suppressor in the development of this tumor. They also confirmed this role in a basal cell carcinoma from the same individual. They suggested that Gorlin syndrome is more common than previously recognized and may not be diagnosed on clinical grounds alone even in middle life. In their Table 1 they provided diagnostic criteria for Gorlin syndrome. Five major and 6 minor criteria were listed. A positive diagnosis can be made, they suggested, on the basis of 2 major or 1 major and 2 minor criteria. Major criteria included multiple (more than 2) BCCs or 1 before age 30 years, or more than 10 basal cell nevi; any odontogenic keratocyst or polyostotic bone cyst; palmar and plantar pits; ectopic calcification; and a family history of NBCCS. Minor criteria included rib or vertebral anomalies; large head circumference with frontal bossing; cardiac or ovarian fibroma; and lymphomesenteric cysts. Falx calcification under the age of 20 years and palmar or plantar pits were among the major criteria. </p><p>Studying patients who presented with multiple odontogenic keratocysts, Lench et al. (1997) identified 5 novel germline mutations in PTCH. Four mutations caused premature stop codons and 1 resulted in an amino acid substitution toward the C terminus of the predicted protein. </p><p>Wicking et al. (1997) presented an additional 4 novel PTCH mutations in nevoid basal cell carcinoma syndrome, having previously reported 28 mutations. They identified 8 individuals who carried a de novo mutation in the PTCH gene. In 5 of these cases, clinical and radiologic examination had not unequivocally ruled out a diagnosis in one of the parents. On the basis of the findings in the parents, Wicking et al. (1997) presented the following review of diagnostic criteria for this syndrome: (1) although palmar and plantar pitting is pathognomonic of NBCCS, it can be falsely reported; (2) a caution must be exercised in using 'multiple BCC' as a diagnostic criterion, especially in areas of high sun exposure; (3) high-arched palate, a minor diagnostic anomaly, is quite common in the general population; and (4) a dense calcification of the falx was not found in these parents, but is an almost invariable finding in adults with mutations in the PTCH gene. </p><p>Aszterbaum et al. (1998) screened the 23 exons of the PTCH gene for mutations by use of single-strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and 7 basal cell nevus syndrome-associated basal cell carcinomas. This screen identified mutations located in 8 exons in 13 of the basal cell nevus syndrome patients and in 3 of the tumors. The most common mutations were frameshifts resulting in premature chain termination. Of 26 sporadic basal cell carcinomas screened, 11 showed loss of heterozygosity at 1 or more of the polymorphic markers examined in the PTCH gene region. Of these 11, 3 tumors were found to have PTCH gene mutations, each in a different exon of the gene. One of these was predicted to result in an amino acid substitution, 1 in a premature stop codon, and 1 in a frameshift. The latter 2 mutations caused premature chain termination. These 3 mutations were not those considered to be characteristic of UV-induced changes. </p><p>Bodak et al. (1999) analyzed the PTCH gene, which had been postulated to be a tumor suppressor gene, in 22 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP; see 278700). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. The data confirmed the presence of high levels of UV-induced mutations (C-to-T or CC-to-TT transitions), all located at the bipyrimidine sites in the PTCH gene. Moreover, in 7 of 14 (50%) BCCs from patients with XP, both PTCH and p53 (191170) were mutated. </p><p>Matt et al. (2000) studied 29 randomly selected cases of sporadic trichoepithelioma (see 601606) by microdissection and PCR using paraffin-embedded, formalin-fixed tissue specimens on glass slides. Analysis was performed with the polymorphic markers IFNA and D9S171 (9p21) as well as D9S15, D9S303, D9S287, and D9S252 (9q22.3). Loss of heterozygosity (LOH) at 9q22.3 including the Patched gene was identified in 14 (48%) of 29 cases with at least 1 marker, but could not be demonstrated in any case using the markers IFNA or D9S171 (9p21). </p><p>Strange et al. (2004) presented evidence that polymorphisms in the PTCH gene are associated with susceptibility to BCC. They concluded that the association was not mediated by the extent of exposure to ultraviolet radiation. </p><p>Lindstrom et al. (2006) analyzed the distribution of mutations in the PTCH1 gene underlying the nevoid basal cell carcinoma syndrome and in many different sporadic tumors in which PTCH1 appears to act as a tumor suppressor gene. Sporadic medulloblastomas were among the more frequent of the latter group. Among a group of 152 sporadic tumors, the number of sporadic medulloblastoma mutations was relatively small (23), with 65% nonsense, 22% missense, and 13% putative splice. </p><p>Takahashi et al. (2009) identified 6 different heterozygous truncating germline mutations in the PTCH1 gene in 6 Japanese families with BCNS1. There was no evidence of a founder effect. </p><p>Using genomic DNA extracted from the blood of a 21-year-old Japanese woman with palmoplantar pits and multiple jaw cysts, Nakamura and Tokura (2009) directly sequenced the PTCH1 gene and identified heterozygosity for a missense mutation (V442E; 601309.0018). Her unaffected parents and an affected brother and sister did not participate in the study. The mutation was not found in the Japanese SNP database. The authors noted that although Japan is a genetically closed island, no founder effect had been observed among Japanese NBCCS patients. </p><p><strong><em>Holoprosencephaly 7</em></strong></p><p>
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Holoprosencephaly-3 (HPE3; 142945) is caused by haploinsufficiency for the Sonic hedgehog gene (SHH; 600725). Ming et al. (2002) hypothesized that mutations in genes encoding components of the SHH signaling pathway also could be associated with holoprosencephaly. PTCH, the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. Ming et al. (2002) identified 4 different mutations in PTCH (601309.0011-601309.0014) in 5 unrelated affected individuals with holoprosencephaly-7 (HPE7; 610828). They predicted that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations caused decreased SHH signaling, with resulting HPE. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. The findings demonstrated further genetic heterogeneity associated with the HPE phenotype, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical disorder. </p><p>Ribeiro et al. (2006) identified 4 different mutations (see, e.g., 601309.0015) in 5 Brazilian probands, 4 with HPE and 1 with HPE-like facial features with normal MRI. One of the patients reported by Ribeiro et al. (2006) was described by Guion-Almeida et al. (2007) as having cerebrooculonasal syndrome (CONS; 605627) (see 601309.0015). </p><p>In a 5-year-old Brazilian girl with holoprosencephaly-like phenotype (610828), Rahimov et al. (2006) identified double heterozygosity for a mutation in the PTCH1 gene (601309.0012) and a mutation in the GLI2 gene (165230.0003). </p><p>Derwinska et al. (2009) identified a 360-kb duplication encompassing the entire PTCH1 gene in a mother and son with microcephaly, mild developmental delay, and mild dysmorphic features. The mother had 7 previous miscarriages. The authors postulated that a gain of function of PTCH1 may be involved in a holoprosencephaly-like phenotype, which includes microcephaly. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In a cohort of 22 patients with ocular developmental anomalies (ODA), Chassaing et al. (2016) identified 4 unrelated patients with a heterozygous variant predicted to be deleterious by in silico analysis in the PTCH1 gene. One patient (P5) with microphthalmia, cataract, and sclerocornea had a frameshift deletion (c.4delG, Glu2AsnfsTer9); 1 patient (P20) with bilateral Peters anomaly had a missense mutation (Y1316C); and 2 patients (P8 and P15) with colobomatous microphthalmia, corpus callosum abnormality, and atrial septal defects had missense mutations (T1064M and V1081M, respectively). With the exception of P5, for whom the authors were unable to perform segregation analysis, the mutation was inherited from an asymptomatic parent. Screening for additional mutations in the PTCH1 gene in the remaining patients identified an additional patient (P17) with Axenfeld-Rieger malformation who had a missense mutation (R1297W). In another cohort of 48 patients with ODA, Chassaing et al. (2016) identified 2 more heterozygous PTCH1 mutations: I899V in a patient (CC10) with bilateral Peters anomaly, and T778P in a patient (CC44) with anophthalmia/microphthalmia and anterior segment dysgenesis. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Goodrich et al. (1997) investigated the function of the ptc gene by inactivating the gene in mice by homologous recombination in ES cells. Mice homozygous for the mutation died during embryogenesis and were found to have open and overgrown neural tubes. Two Sonic hedgehog (Shh) target genes, ptc itself and Gli (165220), were derepressed in the ectoderm and mesoderm but not in the endoderm. Shh targets that are, under normal conditions, transcribed ventrally were aberrantly expressed in dorsal and lateral neural tube cells. Goodrich et al. (1997) concluded that ptc is essential for repression of genes that are locally activated by Shh. Mice heterozygous for the ptch mutation were larger than normal, and a subset of them developed hindlimb defects (including extra digits, syndactyly and soft tissue tumors) or cerebellar medulloblastomas, abnormalities also seen in patients with the basal cell nevus syndrome. The authors speculated that their failure to observe basal cell carcinomas in the heterozygous mice may have been because somatic inactivation of the second ptc gene is required as it is in human basal cell carcinomas. </p><p>Black et al. (2003) showed that PtchlacZ +/- mice exhibited vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ +/- mice exhibited abnormal cell cycle regulation, which culminated in photoreceptor dysplasia and Muller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs can cause significant visual loss in the general, especially elderly, population. Black et al. (2003) hypothesized that alteration of Muller cell Hh signaling may play a role in the pathogenesis of such age-related 'idiopathic' ERMs. </p><p>Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas induced by an activated Ras oncogene (see Hras, 190020), whereas FVB/N mice are highly susceptible. Wakabayashi et al. (2007) demonstrated that susceptibility to squamous cell carcinoma is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains are resistant to Ras-induced squamous cell carcinomas, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch-B6) or by overexpression of the FVB/N Ptch allele (Ptch-FVB) in the epidermis of K5Hras-transgenic F1 hybrid mice. The human Patched gene is a classic tumor suppressor gene for all basal cell carcinomas and medulloblastomas, the loss of which causes increased signaling through the SHH pathway. Squamous cell carcinomas that develop in Ptch-B6 heterozygous mice do not lose the wildtype Ptch gene or show evidence of increased SHH signaling. Although Ptch-FVB overexpression can promote squamous cell carcinoma formation, continued expression is not required for tumor maintenance, suggesting a role at an early stage of tumor cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis and binding to Tid1 (608382), the mouse homolog of the Drosophila l(2)tid tumor suppressor gene. Wakabayashi et al. (2007) proposed that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumor types can arise from the same target cell depending on carcinogen exposure and host genetic background. </p><p>Ohba et al. (2008) found that adult Ptch1 +/- mice had higher bone mass than adult wildtype mice. In culture, Ptch1 +/- cells showed accelerated osteoblast differentiation, enhanced responsiveness to Runx2 (600211), and reduced generation of the repressor form of Gli3 (165240). Administration of a hedgehog signaling inhibitor decreased bone mass in adult wildtype mice. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>18 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 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 9-BP INS, CODON 815, PRO-ASN-ILE INS
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<br />
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SNP: rs1588568813,
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ClinVar: RCV001015535, RCV001072024, RCV004553555, RCV004576978
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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 49-year-old man with basal cell nevus syndrome (BCNS1; 109400), Johnson et al. (1996) identified a 9-bp insertion (CCGAATATC) in the PTCH gene. The heterozygous mutation results in the insertion of proline, asparagine, and isoleucine after codon 815 in exon 15 of the gene and is a tandem duplication of 3 amino acids of the normal polypeptide. The patient's affected sister and daughter had the same alteration, but 3 unaffected relatives did not. </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 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 11-BP DEL, NT2442
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<br />
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SNP: rs2117956624,
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ClinVar: RCV004576889
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 18-year-old woman with basal cell nevus syndrome (BCNS1; 109400), Johnson et al. (1996) identified an 11-bp deletion in exon 15 of the PTCH gene. The deletion removes nucleotides 2442 to 2452 from the coding sequence, resulting in an ORF with 9 C-terminal missense codons and a stop signal at codon 823. The patient developed BCC at age 6 years and jaw cysts at age 8. The patient was heterozygous for this mutation and was the first affected member of this family, since her parents had neither BCCs nor other signs of BCNS. </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 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, GLN210TER
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<br />
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SNP: rs267606984,
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ClinVar: RCV000144436, RCV004576922
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous C-to-T transition (1081C-T) in the codon for gln210 of PTCH which led to a premature stop codon in exon 8. </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 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 37-BP DEL, NT808
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<br />
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SNP: rs2118419579,
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ClinVar: RCV004576890
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous 37-bp deletion (808_840del) in exon 6 of the PTCH gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 1148G-A
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<br />
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SNP: rs2118365442,
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ClinVar: RCV000008698, RCV004576891
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous G-to-A transition (1148G-A) in exon 8 of the PTCH gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 2-BP INS, 2047CT
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<br />
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SNP: rs2118041703,
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ClinVar: RCV004576892
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous 2-bp insertion at nucleotide 2047 (2047insCT) in exon 13 of the PTCH gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 BASAL CELL NEVUS SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 1-BP INS, 2000C
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<br />
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SNP: rs1554695110,
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ClinVar: RCV000277549, RCV001804162, RCV004576942
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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 basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous 1-bp insertion (2000insC) in exon 13 of the PTCH gene, resulting in a premature stop 9 amino acids downstream. The parents did not have the mutation and were free of phenotypic features of BCNS. </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>.0008 BASAL CELL NEVUS SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PTCH1, 1-BP DEL, 2583C
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<br />
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SNP: rs2136689212,
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ClinVar: RCV004576893
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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 basal cell nevus syndrome (BCNS1; 109400), Hahn et al. (1996) identified a heterozygous 1-bp deletion (2583delC) in exon 15 of the PTCH gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 BASAL CELL CARCINOMA, SOMATIC</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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PTCH1, 451C-T, PRO-SER
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<br />
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ClinVar: RCV000008702
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In the DNA from a somatic basal cell carcinoma (see 605462) from the cheek, Gailani et al. (1996) found a 451C-T transition in exon 3 of the PTCH1 gene, predicted to result in a pro-to-ser amino acid substitution. LOH in chromosome 9 was also demonstrated. This was 1 of 12 mutations detected by Gailani et al. (1996) in 37 sporadic BCCs studied. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 BASAL CELL CARCINOMA, SOMATIC</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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PTCH1, 3340A-T, ARG-TRP
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<br />
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SNP: rs587776689,
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ClinVar: RCV000008703
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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>Of the 3 somatic basal cell carcinomas (see 605462) in which Aszterbaum et al. (1998) found a PTCH mutation, one had a heterozygous 3340A-T transversion in exon 10, predicted to result in an arg-to-trp amino acid change. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 HOLOPROSENCEPHALY 7</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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PTCH1, ALA393THR
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<br />
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SNP: rs199476091,
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gnomAD: rs199476091,
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ClinVar: RCV000008704, RCV000532256, RCV001010144, RCV004547466
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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 female with holoprosencephaly (HPE7; 610828), Ming et al. (2002) identified a heterozygous 1165G-A transition in the PTCH gene, resulting in an ala393-to-thr (A393T) substitution in an extracellular loop of the PTCH protein. The variant was also present in her clinically normal father. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0012 HOLOPROSENCEPHALY 7</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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PTCH1, THR728MET
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<br />
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SNP: rs115556836,
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gnomAD: rs115556836,
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ClinVar: RCV000008705, RCV000034564, RCV000078462, RCV000206005, RCV000568375, RCV002504769
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated probands with holoprosencephaly-7 (HPE7; 610828), Ming et al. (2002) found a 2171C-T transition in the PTCH gene, resulting in a thr728-to-met (T728M) amino acid substitution in an intracellular loop of the PTCH protein. In 1 family, the female proband had semilobar HPE, absence of the corpus callosum, and fusion of the thalami. Her brother had a single central maxillary incisor, bilateral cleft lip/palate, and developmental delay. Their clinically normal mother did not carry the mutation, and their father was not available for testing. In the second family, the female proband had HPE and partial agenesis of the corpus callosum, panhypopituitarism, midline cleft lip and palate, a small omphalocele, and mild to moderate developmental delay. Her phenotypically normal mother did not have the mutation, and the girl's father was not available for testing. </p><p>In a 5-year-old Brazilian girl with a holoprosencephaly-like phenotype, Rahimov et al. (2006) identified double heterozygosity for the T728M mutation and an R151G mutation in the GLI2 gene (165230.0003). (The authors erroneously stated that the 2171C-T transition resulted in a T328M substitution.) Clinical features included large ears, hypoplastic anterior nasal spine, diminished frontonasal angle, hypotelorism, hypoplastic premaxilla, hypoplastic nose with flattened alae and nasal tip, poorly developed philtrum, bilateral cleft lip/palate, malocclusion, and normal neuropsychologic development. MRI demonstrated mild gyral asymmetry in the perisylvian areas. The causative nature of the GLI2 mutation was uncertain. </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>.0013 HOLOPROSENCEPHALY 7</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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PTCH1, SER827GLY
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<br />
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SNP: rs199476092,
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gnomAD: rs199476092,
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|
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ClinVar: RCV000008706, RCV000034565, RCV000121886, RCV000563051, RCV001083878, RCV004547467
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|
|
</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female with holoprosencephaly, seizures, and bilateral cleft lip (HPE7; 610828), Ming et al. (2002) found a heterozygous 2467A-G transition in the PTCH gene, resulting in a ser827-to-gly (S827G) substitution in an extracellular loop of the protein. The clinically normal mother also had the 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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HOLOPROSENCEPHALY 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
PTCH1, THR1052MET
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<br />
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|
|
SNP: rs138911275,
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|
|
|
|
|
gnomAD: rs138911275,
|
|
|
|
|
|
ClinVar: RCV000008707, RCV000034570, RCV000121888, RCV000148761, RCV000574977, RCV001081022, RCV004547468
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male with alobar holoprosencephaly and hypotelorism and in his brother with hypotelorism and developmental delay (HPE7; 610828), Ming et al. (2002) found a heterozygous 3143C-T transition in the PTCH gene resulting in a thr1052-to-met (T1052M) amino acid substitution in an intracellular loop of the PTCH protein. Their clinically normal father also carried the mutation; their sister and mother, both of whom had normal cognitive development, did not carry the mutation. </p><p>Ribeiro et al. (2006) described the T1052M mutation in a Brazilian girl with holoprosencephaly-like facial features but normal MRI. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HOLOPROSENCEPHALY 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTCH1, VAL908GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199476093,
|
|
|
|
|
|
|
|
ClinVar: RCV000008708
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Brazilian female patients with holoprosencephaly-7 (HPE7; 610828), Ribeiro et al. (2006) identified a 2711G-T transversion in exon 17 of the PTCH1 gene, resulting in a val908-to-gly (V908G) substitution in an extracellular domain. The 2 patients differed phenotypically: one had alobar HPE, absent nasal septum, and midline cleft lip-palate, and the other had lobar HPE, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other. The former patient died at 6 months of age. The second patient was reported by Guion-Almeida et al. (2007) as having cerebrooculonasal syndrome (605627). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 BASAL CELL NEVUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTCH1, 1-BP INS, 1247T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2118336503,
|
|
|
|
|
|
|
|
ClinVar: RCV000008709, RCV004576894
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old Japanese girl with basal cell nevus syndrome (BCNS1; 109400) and ulcerative colitis (see 266600), Fujii et al. (2003) identified a 1-bp insertion (T) at nucleotide 1247 in exon 9 of the PTCH1 gene, resulting in premature termination of the protein. Ohba et al. (2008) found that the bone mineral density of the lumbar spine and femoral neck of this patient was elevated compared with an age- and gender-matched control, consistent with their findings in Ptch1 +/- mice. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 BASAL CELL NEVUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTCH1, TRP129TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1587692888,
|
|
|
|
|
|
|
|
ClinVar: RCV000030726, RCV004576912
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old boy with basal cell nevus syndrome (BCNS1; 109400), Suzuki et al. (2012) identified a de novo heterozygous 387G-A transition in exon 2 of the PTCH1 gene, resulting in a trp129-to-ter (W129X) substitution. RT-PCR and protein translation studies indicated that the mutant allele was translated from the second initiation codon in exon 3, generating the short PTCH1 isoform, whereas the PTCHM isoform was degraded. The findings indicated that the phenotype resulted from selective haploinsufficiency of PTCHL and PTCHM, but not PTCHS. The patient had palmar and plantar pits, calcification of the falx cerebri, and keratocystic odontogenic tumor. He also had macrocephaly and scoliosis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 BASAL CELL NEVUS SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PTCH1, VAL442GLU
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV004577311
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 21-year-old Japanese woman with palmoplantar pits and multiple jaw cysts (BCNS1; 109400), Nakamura and Tokura (2009) directly sequenced the PTCH1 gene and identified heterozygosity for a c.1325T-A transversion in exon 9, resulting in a val442-to-glu (V442E) substitution within the second transmembrane domain. Her unaffected parents and an affected brother and sister did not participate in the study. The mutation was not found in the Japanese SNP database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
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|
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|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
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<div>
|
|
<ol>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Aszterbaum, M., Rothman, A., Johnson, R. L., Fisher, M., Xie, J., Bonifas, J. M., Zhang, X., Scott, M. P., Epstein, E. H., Jr.
|
|
<strong>Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.</strong>
|
|
J. Invest. Derm. 110: 885-888, 1998.
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|
|
[PubMed: 9620294]
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|
|
[Full Text: https://doi.org/10.1046/j.1523-1747.1998.00222.x]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bale, A. E., Yu, K.-P.
|
|
<strong>The hedgehog pathway and basal cell carcinomas.</strong>
|
|
Hum. Molec. Genet. 10: 757-762, 2001.
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|
[PubMed: 11257109]
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|
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[Full Text: https://doi.org/10.1093/hmg/10.7.757]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Bale, A. E.
|
|
<strong>Variable expressivity of Patched mutations in flies and humans. (Editorial)</strong>
|
|
Am. J. Hum. Genet. 60: 10-12, 1997.
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|
[PubMed: 8981940]
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</p>
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|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Black, G. C. M., Mazerolle, C. J., Wang, Y., Campsall, K. D., Petrin, D., Leonard, B. C., Damji, K. F., Evans, D. G., McLeod, D., Wallace, V. A.
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<strong>Abnormalities of the vitreoretinal interface caused by dysregulated hedgehog signaling during retinal development.</strong>
|
|
Hum. Molec. Genet. 12: 3269-3276, 2003.
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[PubMed: 14570707]
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[Full Text: https://doi.org/10.1093/hmg/ddg356]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bodak, N., Queille, S., Avril, M. F., Bouadjar, B., Drougard, C., Sarasin, A., Daya-Grosjean, L.
|
|
<strong>High levels of Patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.</strong>
|
|
Proc. Nat. Acad. Sci. 96: 5117-5122, 1999.
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|
|
[PubMed: 10220428]
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[Full Text: https://doi.org/10.1073/pnas.96.9.5117]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Casali, A., Struhl, G.
|
|
<strong>Reading the hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein.</strong>
|
|
Nature 431: 76-80, 2004.
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[PubMed: 15300262]
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[Full Text: https://doi.org/10.1038/nature02835]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Chassaing, N., Davis, E. E., McKnight, K. L., Niederriter, A. R., Causse, A., David, V., Desmaison, A., Lamarre, S., Vincent-Delorme, C., Pasquier, L., Coubes, C., Lacombe, D., Rossi, M., Dufier, J.-L., Dollfus, H., Kaplan, J., Katsanis, N., Etchevers, H. C., Faguer, S., Calvas, P.
|
|
<strong>Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.</strong>
|
|
Genome Res. 26: 474-485, 2016.
|
|
|
|
|
|
[PubMed: 26893459]
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|
|
[Full Text: https://doi.org/10.1101/gr.196048.115]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Chen, W., Ren, X.-R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., Lefkowitz, R. J.
|
|
<strong>Activity-dependent internalization of Smoothened mediated by beta-arrestin 2 and GRK2.</strong>
|
|
Science 306: 2257-2260, 2004.
|
|
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|
|
[PubMed: 15618519]
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[Full Text: https://doi.org/10.1126/science.1104135]
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</p>
|
|
</li>
|
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|
<li>
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Strange, R. C., El-Genidy, N., Ramachandran, S., Lovatt, T. J., Fryer, A. A., Smith, A. G., Lear, J. T., Wong, C., Jones, P. W., Ichii-Jones, F., Hoban, P. R.
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Suzuki, M., Hatsuse, H., Nagao, K., Takayama, Y., Kameyama, K., Kabasawa, Y., Omura, K., Yoshida, M., Fujii, K., Miyashita, T.
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Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., Beachy, P. A.
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<strong>Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.</strong>
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Nature 406: 1005-1009, 2000.
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[PubMed: 10984056]
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Taipale, J., Cooper, M. K., Maiti, T., Beachy, P. A.
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<strong>Patched acts catalytically to suppress the activity of Smoothened.</strong>
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Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.
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Takahashi, C., Kanazawa, N., Yoshikawa, Y., Yoshikawa, R., Saitoh, Y., Chiyo, H., Tanizawa, T., Hashimoto-Tamaoki, T., Nakano, Y.
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Thibert, C., Teillet, M.-A., Lapointe, F., Mazelin, L., Le Douarin, N. M., Mehlen, P.
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<strong>Inhibition of neuroepithelial Patched-induced apoptosis by Sonic hedgehog.</strong>
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Science 301: 843-846, 2003.
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[PubMed: 12907805]
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Wakabayashi, Y., Mao, J.-H., Brown, K., Girardi, M., Balmain, A.
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<strong>Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.</strong>
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Nature 445: 761-765, 2007.
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Wicking, C., Gillies, S., Smyth, I., Shanley, S., Fowles, L., Ratcliffe, J., Wainwright, B., Chenevix-Trench, G.
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<strong>De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.</strong>
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Wicking, C., Shanley, S., Smyth, I., Gillies, S., Negus, K., Graham, S., Suthers, G., Haites, N., Edwards, M., Wainwright, B., Chenevix-Trench, G.
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<strong>Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.</strong>
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Contributors:
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Marla J. F. O'Neill - updated : 06/12/2024<br>Marla J. F. O'Neill - updated : 01/19/2022<br>Bao Lige - updated : 08/27/2021<br>Ada Hamosh - updated : 11/26/2018<br>Ada Hamosh - updated : 09/21/2018<br>Ada Hamosh - updated : 4/5/2016<br>Patricia A. Hartz - updated : 4/1/2016<br>Ada Hamosh - updated : 8/6/2014<br>Ada Hamosh - updated : 8/6/2014<br>Ada Hamosh - updated : 1/30/2014<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 1/7/2010<br>Nara Sobreira - updated : 9/9/2009<br>Cassandra L. Kniffin - updated : 8/31/2009<br>Ada Hamosh - updated : 5/12/2009<br>Patricia A. Hartz - updated : 10/9/2008<br>Ada Hamosh - updated : 8/20/2007<br>Ada Hamosh - updated : 6/26/2007<br>Victor A. McKusick - updated : 2/23/2007<br>Victor A. McKusick - updated : 4/28/2006<br>George E. Tiller - updated : 1/10/2006<br>Patricia A. Hartz - updated : 5/4/2005<br>Victor A. McKusick - updated : 3/15/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 11/10/2004<br>Ada Hamosh - updated : 9/15/2003<br>Ada Hamosh - updated : 9/13/2002<br>Ada Hamosh - updated : 9/10/2002<br>Victor A. McKusick - updated : 5/13/2002<br>George E. Tiller - updated : 6/19/2001<br>Ada Hamosh - updated : 9/1/2000<br>Victor A. McKusick - updated : 2/18/2000<br>Victor A. McKusick - updated : 9/15/1998<br>Victor A. McKusick - updated : 12/30/1997<br>Victor A. McKusick - updated : 10/7/1997<br>Victor A. McKusick - updated : 9/16/1997<br>Victor A. McKusick - updated : 8/27/1997<br>Moyra Smith - updated : 1/24/1997<br>Mark H. Paalman - updated : 12/3/1996<br>Moyra Smith - updated : 11/19/1996<br>Moyra Smith - updated : 11/13/1996<br>Moyra Smith - updated : 7/2/1996
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Moyra Smith : 6/14/1996
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