4718 lines
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- *601500 - SMOOTHENED, FRIZZLED CLASS RECEPTOR; SMO
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601500</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601500">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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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<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=ENSG00000128602;t=ENST00000249373" 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=6608" 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=601500" 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 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=ENSG00000128602;t=ENST00000249373" 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_005631,XM_047420759" 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_005631" 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=601500" 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=03294&isoform_id=03294_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/SMO" 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/1813876,3265148,4324955,4732139,5032099,6226142,6940763,14603016,21928430,51094856,119604121,1843476468,2217368268,2462615808" 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/Q99835" 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=6608" 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=ENSG00000128602;t=ENST00000249373" 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=SMO" 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=SMO" 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+6608" 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/SMO" 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:6608" 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/6608" 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=chr7&hgg_gene=ENST00000249373.8&hgg_start=129188633&hgg_end=129213545&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11119" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601500[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=601500[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/SMO/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/ENSG00000128602" 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=SMO" 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=SMO" 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=SMO" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMO&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/PA35968" 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:11119" 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/FBgn0003444.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:108075" 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/SMO#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:108075" 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/6608/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=6608" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-89" 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">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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|
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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:6608" 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=SMO&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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601500
|
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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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SMOOTHENED, FRIZZLED CLASS RECEPTOR; SMO
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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>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SMOOTHENED, DROSOPHILA, HOMOLOG OF; SMOH
|
|
</span>
|
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</h4>
|
|
</div>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMO" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMO</a></em></strong>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/665?start=-3&limit=10&highlight=665">7q32.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:129188633-129213545&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'})">7:129,188,633-129,213,545</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=605462,601707,241800" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/665?start=-3&limit=10&highlight=665">
|
|
7q32.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Basal cell carcinoma, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/605462"> 605462 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
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|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Curry-Jones syndrome, somatic mosaic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/601707"> 601707 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pallister-Hall-like syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/241800"> 241800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
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|
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</tbody>
|
|
</table>
|
|
</div>
|
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</div>
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<div>
|
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<p>SMO is a positive effector of the SHH (<a href="/entry/600725">600725</a>) signaling pathway (summary by <a href="#16" class="mim-tip-reference" title="Purcell, P., Joo, B. W., Hu, J. K., Tran, P. V., Calicchio, M. L., O'Connell, D. J., Maas, R. L., Tabin, C. J. <strong>Temporomandibular joint formation requires two distinct hedgehog-dependent steps.</strong> Proc. Nat. Acad. Sci. 106: 18297-18302, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815519</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815519[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.0908836106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19815519">Purcell et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19815519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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> screened a rat embryonic library with the Drosophila 'Smoothened' (Smo) gene and isolated overlapping cDNA clones which encoded a protein of 794 amino acids. Subsequently they isolated a human homolog of the Drosophila Smo gene, which is 94% homologous to the rat gene. The rat and human SMO genes are 33% homologous to Drosophila Smo; in the putative transmembrane domains of the gene homology is 50%. <a href="#21" 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> reported that human and rat SMO appear to be 7-transmembrane G protein-coupled receptors with 4 glycosylation sites and a putative extracellular amino terminus 203-205 amino acids long which includes 13 cysteines and can bind a polypeptide ligand. They observed that the spatial distribution of the rat 'Patched' gene product PTC (<a href="/entry/601309">601309</a>) and SMO show considerable overlap in embryonic tissues. <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>
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<p><a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> reported that the SMO locus spans more than 35 kb of genomic DNA. They found that the SMO gene contains 12 exons within 24 kb of genomic DNA. Exons 1 and 2 contain 5-prime untranslated sequences, the initiation codon ATG, and the entire signal peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By fluorescence in situ hybridization (FISH), <a href="#18" class="mim-tip-reference" title="Quirk, J., van den Heuvel, M., Henrique, D., Marigo, V., Jones, T. A., Tabin, C., Ingham, P. W. <strong>The Smoothened gene and hedgehog signal transduction in Drosophila and vertebrate development.</strong> Cold Spring Harbor Symp. Quant. Biol. 62: 217-226, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598354</a>]" pmid="9598354">Quirk et al. (1997)</a> mapped the human SMO gene to 7q32. By the same method, <a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> mapped the gene to 7q31-q32. By FISH and radiation hybrid analysis, <a href="#22" class="mim-tip-reference" title="Sublett, J. E., Entrekin, R. E., Look, A. T., Reardon, D. A. <strong>Chromosomal localization of the human Smoothened gene (SMOH) to 7q32.3 by fluorescence in situ hybridization and radiation hybrid mapping.</strong> Genomics 50: 112-114, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9628830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9628830</a>] [<a href="https://doi.org/10.1006/geno.1998.5227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9628830">Sublett et al. (1998)</a> refined the localization to 7q32.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9422511+9628830+9598354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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> carried out competitor binding, crosslinking, and coprecipitation studies and demonstrated that there was no evidence that Smo acted as a receptor for Shh, the Sonic hedgehog gene product. They demonstrated that an epitope-tagged N-terminal Shh peptide binds specifically to mouse Ptc (<a href="/entry/601309">601309</a>). They also showed that Ptc and Smo form a complex to which Shh binds. <a href="#21" 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> noted that genetic mutations leading to a truncated or unstable Ptc protein are associated with the familial or sporadic form of basal cell carcinoma (BCC). This finding, combined with the fact that Ptc is a high-affinity binding protein for Shh, suggests that the hedgehog system may provide mitogenic or differentiative signals to basal cells in the skin throughout life. <a href="#21" 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> raised the possibility that BCNS (<a href="/entry/109400">109400</a>) and BCC might result from constitutive activation of SMO, which then 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="#3" 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 induce Smo activity. <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><a href="#24" 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="#24" 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="#24" 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><a href="#2" 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 Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by Grk2 and interaction of Arrb2 with Smo. <a href="#2" 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="#12" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> showed that PKA (see <a href="/entry/188830">188830</a>) and casein kinase I (CKI; <a href="/entry/600505">600505</a>) regulate Smo cell surface accumulation and activity in response to hedgehog (Hh; see Shh, <a href="/entry/600725">600725</a>). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. <a href="#12" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, <a href="#12" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. <a href="#12" class="mim-tip-reference" title="Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J. <strong>Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.</strong> Nature 432: 1045-1050, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616566</a>] [<a href="https://doi.org/10.1038/nature03179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616566">Jia et al. (2004)</a> concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y. R., Reiter, J. F. <strong>Vertebrate Smoothened functions at the primary cilium.</strong> Nature 437: 1018-1021, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16136078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16136078</a>] [<a href="https://doi.org/10.1038/nature04117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16136078">Corbit et al. (2005)</a> showed that mammalian Smo is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Shh or activating mutations in Smo promoted ciliary localization, whereas the Smo antagonist cyclopamine inhibited ciliary localization. They showed that the translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain shown to be required for the ciliary localization of 7-transmembrane proteins in C. elegans. Mutation of this domain not only prevented ciliary localization but also eliminated Smo activity both in cultured cells and in zebrafish embryos. Thus, <a href="#5" class="mim-tip-reference" title="Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y. R., Reiter, J. F. <strong>Vertebrate Smoothened functions at the primary cilium.</strong> Nature 437: 1018-1021, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16136078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16136078</a>] [<a href="https://doi.org/10.1038/nature04117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16136078">Corbit et al. (2005)</a> concluded that Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16136078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 an assay for G protein activation sensitive for receptor-constitutive activity, <a href="#19" class="mim-tip-reference" title="Riobo, N. A., Saucy, B., DiLizio, C., Manning, D. R. <strong>Activation of heterotrimeric G proteins by Smoothened.</strong> Proc. Nat. Acad. Sci. 103: 12607-12612, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16885213[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.0600880103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885213">Riobo et al. (2006)</a> found that mouse Smo coupled with all members of the Gi family (see <a href="/entry/139310">139310</a>), but not with members of other G protein families. Inhibitors of hedgehog signaling blocked coupling of Smo with Gi. In addition, Gi and the C-terminal tail of Smo were required for activation of Gli (<a href="/entry/165220">165220</a>). <a href="#19" class="mim-tip-reference" title="Riobo, N. A., Saucy, B., DiLizio, C., Manning, D. R. <strong>Activation of heterotrimeric G proteins by Smoothened.</strong> Proc. Nat. Acad. Sci. 103: 12607-12612, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16885213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16885213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16885213[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.0600880103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16885213">Riobo et al. (2006)</a> proposed that SMO is the source of 2 signals, one operating through Gi and the other originating with the SMO C-terminal tail, that are required for activation of GLI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16885213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#35" class="mim-tip-reference" title="Zhao, Y., Tong, C., Jiang, J. <strong>Hedgehog regulates smoothened activity by inducing a conformational switch.</strong> Nature 450: 252-258, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960137</a>] [<a href="https://doi.org/10.1038/nature06225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960137">Zhao et al. (2007)</a> provided evidence that phosphorylation by hedgehog activates SMO by inducing a conformational switch in Drosophila melanogaster. This occurs by antagonizing multiple arg clusters in the SMO cytoplasmic tail. The arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. Hedgehog-induced phosphorylation disrupts the interaction and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. <a href="#35" class="mim-tip-reference" title="Zhao, Y., Tong, C., Jiang, J. <strong>Hedgehog regulates smoothened activity by inducing a conformational switch.</strong> Nature 450: 252-258, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960137</a>] [<a href="https://doi.org/10.1038/nature06225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960137">Zhao et al. (2007)</a> found that increasing the number of mutations in the arg clusters progressively activated SMO. <a href="#35" class="mim-tip-reference" title="Zhao, Y., Tong, C., Jiang, J. <strong>Hedgehog regulates smoothened activity by inducing a conformational switch.</strong> Nature 450: 252-258, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960137</a>] [<a href="https://doi.org/10.1038/nature06225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17960137">Zhao et al. (2007)</a> concluded that by employing multiple arg clusters as inhibitory elements counteracted by differential phosphorylation, SMO acts as a rheostat to translate graded HH signals into distinct responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17960137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kovacs, J. J., Whalen, E. J., Liu, R., Xiao, K., Kim, J., Chen, M., Wang, J., Chen, W., Lefkowitz, R. J. <strong>Beta-arrestin-mediated localization of Smoothened to the primary cilium.</strong> Science 320: 1777-1781, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18497258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18497258</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18497258[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.1157983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18497258">Kovacs et al. (2008)</a> demonstrated that beta-arrestins mediate the activity-dependent interaction of SMO and the kinesin motor protein KIF3A (<a href="/entry/604683">604683</a>). This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. Beta-arrestin-1 (<a href="/entry/107940">107940</a>) or beta-arrestin-2 (<a href="/entry/107941">107941</a>) depletion prevented the localization of SMO to primary cilia and the SMO-dependent activation of GLI (<a href="/entry/165220">165220</a>). <a href="#13" class="mim-tip-reference" title="Kovacs, J. J., Whalen, E. J., Liu, R., Xiao, K., Kim, J., Chen, M., Wang, J., Chen, W., Lefkowitz, R. J. <strong>Beta-arrestin-mediated localization of Smoothened to the primary cilium.</strong> Science 320: 1777-1781, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18497258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18497258</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18497258[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.1157983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18497258">Kovacs et al. (2008)</a> concluded that their results suggested roles for beta-arrestin in mediating the intracellular transport of a 7-transmembrane receptor to its obligate subcellular location for signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18497258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Although a cell-autonomous role for hedgehog signaling (see <a href="/entry/600725">600725</a>) in tumors had been described, <a href="#32" class="mim-tip-reference" title="Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., Marshall, D., Fu, L., Januario, T., Kallop, D., Nannini-Pepe, M., Kotkow, K., Marsters, J. C., Jr., Rubin, L. L., de Sauvage, F. J. <strong>A paracrine requirement for hedgehog signalling in cancer.</strong> Nature 455: 406-410, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18754008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18754008</a>] [<a href="https://doi.org/10.1038/nature07275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18754008">Yauch et al. (2008)</a> demonstrated that hedgehog ligands failed to activate signaling in tumor epithelial cells. In contrast, their data supported ligand-dependent activation of the hedgehog pathway in the stromal microenvironment. Specific inhibition of hedgehog signaling using small molecule inhibitors, a neutralizing anti-hedgehog antibody, or genetic deletion of Smo in the mouse stroma resulted in growth inhibition in xenograft tumor models. <a href="#32" class="mim-tip-reference" title="Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., Marshall, D., Fu, L., Januario, T., Kallop, D., Nannini-Pepe, M., Kotkow, K., Marsters, J. C., Jr., Rubin, L. L., de Sauvage, F. J. <strong>A paracrine requirement for hedgehog signalling in cancer.</strong> Nature 455: 406-410, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18754008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18754008</a>] [<a href="https://doi.org/10.1038/nature07275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18754008">Yauch et al. (2008)</a> concluded that their studies demonstrated a paracrine requirement for hedgehog ligand signaling in tumorigenesis of hedgehog-expressing cancers and have important implications for the development of hedgehog pathway antagonists in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18754008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ogden, S. K., Fei, D. L., Schilling, N. S., Ahmed, Y. F., Hwa, J., Robbins, D. J. <strong>G protein G-alpha-i functions immediately downstream of Smoothened in hedgehog signalling.</strong> Nature 456: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18987629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18987629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18987629[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/nature07459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18987629">Ogden et al. (2008)</a> presented in vitro and in vivo evidence in Drosophila that Smoothened activates G-alpha-i (<a href="/entry/139310">139310</a>) to modulate intracellular cAMP levels in response to hedgehog. <a href="#15" class="mim-tip-reference" title="Ogden, S. K., Fei, D. L., Schilling, N. S., Ahmed, Y. F., Hwa, J., Robbins, D. J. <strong>G protein G-alpha-i functions immediately downstream of Smoothened in hedgehog signalling.</strong> Nature 456: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18987629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18987629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18987629[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/nature07459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18987629">Ogden et al. (2008)</a> concluded that Smoothened functions as a canonical G protein-coupled receptor, which signals through GNAI1 to regulate hedgehog pathway activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18987629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T. <strong>Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.</strong> Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19169242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19169242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19169242[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/nature07737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19169242">Zhao et al. (2009)</a> demonstrated that the loss of Smo, an essential component of the hedgehog pathway, impairs hematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia (CML; <a href="/entry/608232">608232</a>) by the BCR-ABL1 (see <a href="/entry/151410">151410</a>) oncoprotein. Loss of Smo causes depletion of CML stem cells, which propagate the leukemia, whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, <a href="#34" class="mim-tip-reference" title="Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T. <strong>Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.</strong> Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19169242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19169242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19169242[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/nature07737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19169242">Zhao et al. (2009)</a> showed that the cell fate determinant Numb (<a href="/entry/603728">603728</a>), which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacologic inhibition of hedgehog signaling impairs not only the propagation of CML driven by wildtype BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. <a href="#34" class="mim-tip-reference" title="Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T. <strong>Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.</strong> Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19169242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19169242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19169242[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/nature07737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19169242">Zhao et al. (2009)</a> concluded that hedgehog pathway activity is required for maintenance of normal and neoplastic stem cells of the hematopoietic system and raised the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19169242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Resistance of Bcr (<a href="/entry/151410">151410</a>)-Abl (<a href="/entry/189980">189980</a>)-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML; <a href="/entry/608232">608232</a>) can cause relapse of disease and might be the origin for emerging drug-resistant clones. <a href="#8" class="mim-tip-reference" title="Dierks, C., Beigi, R., Guo, G.-R., Zirlik, K., Stegert, M. R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., Warmuth, M. <strong>Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation.</strong> Cancer Cell 14: 238-249, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18772113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18772113</a>] [<a href="https://doi.org/10.1016/j.ccr.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18772113">Dierks et al. (2008)</a> identified Smo as a drug target in Bcr-Abl-positive LSCs. They showed that Hedgehog signaling is activated in LSCs through upregulation of Smo. While nullity for Smo does not affect long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacologic Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. <a href="#8" class="mim-tip-reference" title="Dierks, C., Beigi, R., Guo, G.-R., Zirlik, K., Stegert, M. R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., Warmuth, M. <strong>Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation.</strong> Cancer Cell 14: 238-249, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18772113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18772113</a>] [<a href="https://doi.org/10.1016/j.ccr.2008.08.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18772113">Dierks et al. (2008)</a> postulated that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18772113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 a small molecule Smo agonist (SAG), <a href="#26" class="mim-tip-reference" title="Teperino, R., Amann, S., Bayer, M., McGee, S. L., Loipetzberger, A., Connor, T., Jaeger, C., Kammerer, B., Winter, L., Wiche, G., Dalgaard, K., Selvaraj, M., and 9 others. <strong>Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat.</strong> Cell 151: 414-426, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23063129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23063129</a>] [<a href="https://doi.org/10.1016/j.cell.2012.09.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23063129">Teperino et al. (2012)</a> found that Hh signaling rapidly reprogrammed energy metabolism toward aerobic glycolysis in disparate mouse and human cell types. SAG rapidly activated the Smo-AMPK (see <a href="/entry/602739">602739</a>) axis, which was dependent on the primary cilium and was compartmentalized at the cilium base. Treatment with Smo-selective partial agonists of Hh signaling uncoupled canonical and noncanonical Smo signaling and induced metabolic rewiring and acute glucose uptake both in vitro and in vivo. Furthermore, treatment with selective partial agonists drove robust insulin-independent glucose uptake in muscle and brown adipose tissue of mice, because Smo regulated metabolic flux, flexibility, and substrate specificity of exogenous ligand stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23063129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#6" 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 (<a href="/entry/600726">600726</a>), PTCH1 (<a href="/entry/601309">601309</a>), and SMO, 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="#6" 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>
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<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="#23" 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="#23" 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="#23" 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><strong><em>Crystal Structure</em></strong></p><p>
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<a href="#29" class="mim-tip-reference" title="Wang, C., Wu, H., Katritch, V., Han, G. W., Huang, X.-P., Liu, W., Siu, F. Y., Roth, B. L., Cherezov, V., Stevens, R. C. <strong>Structure of the human smoothened receptor bound to an antitumour agent.</strong> Nature 497: 338-343, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23636324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23636324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23636324[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/nature12167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23636324">Wang et al. (2013)</a> reported the crystal structure of the transmembrane domain of the human SMO receptor bound to a small molecule antagonist at 2.5-angstrom resolution. Although the SMO receptor shares the 7-transmembrane helical fold, most of the conserved motifs for class A G protein-coupled receptors (GPCRs) are absent, and the structure revealed an unusually complex arrangement of long extracellular loops stabilized by 4 disulfide bonds. The ligand binds at the extracellular end of the 7-transmembrane-helix bundle and forms extensive contacts with the loops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23636324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Byrne, E. F. X., Sircar, R., Miller, P. S., Hedger, G., Luchetti, G., Nachtergaele, S., Tully, M. D., Mydock-McGrane, L., Covey, D. F., Rambo, R. P., Sansom, M. S. P., Newstead, S., Rohatgi, R., Siebold, C. <strong>Structural basis of Smoothened regulation by its extracellular domains.</strong> Nature 535: 517-522, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27437577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27437577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27437577[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/nature18934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27437577">Byrne et al. (2016)</a> presented the crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains 2 distinct ligand-binding sites: 1 in its transmembrane domain (TMD) and 1 in the cysteine-rich domain (CRD). The CRD is stacked atop the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations showed that the interface between the CRD, linker domain, and TMD stabilizes the inactive state of Smoothened. Unexpectedly, the authors found a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impaired the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induced a conformational change that was propagated to the CRD, resulting in loss of cholesterol from the CRD-linker domain-TMD interface. <a href="#1" class="mim-tip-reference" title="Byrne, E. F. X., Sircar, R., Miller, P. S., Hedger, G., Luchetti, G., Nachtergaele, S., Tully, M. D., Mydock-McGrane, L., Covey, D. F., Rambo, R. P., Sansom, M. S. P., Newstead, S., Rohatgi, R., Siebold, C. <strong>Structural basis of Smoothened regulation by its extracellular domains.</strong> Nature 535: 517-522, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27437577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27437577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27437577[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/nature18934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27437577">Byrne et al. (2016)</a> concluded that their results clarified the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27437577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Deshpande, I., Liang, J., Hedeen, D., Roberts, K. J., Zhang, Y., Ha, B., Latorraca, N. R., Faust, B., Dror, R. O., Beachy, P. A., Myers, B. R., Manglik, A. <strong>Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.</strong> Nature 571: 284-288, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31263273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31263273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31263273[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/s41586-019-1355-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31263273">Deshpande et al. (2019)</a> reported the crystal structure of active mouse Smo bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of Smo was associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models, a cholesterol molecule that is critical for Smo activation is bound deep within the 7-transmembrane pocket. <a href="#7" class="mim-tip-reference" title="Deshpande, I., Liang, J., Hedeen, D., Roberts, K. J., Zhang, Y., Ha, B., Latorraca, N. R., Faust, B., Dror, R. O., Beachy, P. A., Myers, B. R., Manglik, A. <strong>Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.</strong> Nature 571: 284-288, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31263273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31263273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31263273[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/s41586-019-1355-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31263273">Deshpande et al. (2019)</a> proposed that the inactivation of PTCH1 (<a href="/entry/602309">602309</a>) by Hedgehog allows a transmembrane sterol to access this 7-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. <a href="#7" class="mim-tip-reference" title="Deshpande, I., Liang, J., Hedeen, D., Roberts, K. J., Zhang, Y., Ha, B., Latorraca, N. R., Faust, B., Dror, R. O., Beachy, P. A., Myers, B. R., Manglik, A. <strong>Smoothened stimulation by membrane sterols drives Hedgehog pathway activity.</strong> Nature 571: 284-288, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31263273/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31263273</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31263273[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/s41586-019-1355-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31263273">Deshpande et al. (2019)</a> concluded that their results, combined with signaling studies and molecular dynamics simulations, delineated the structural basis for PTCH1-SMO regulation, and suggested a strategy for overcoming clinical resistance to SMO inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31263273" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Qi, X., Liu, H., Thompson, B., McDonald, J., Zhang, C., Li, X. <strong>Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi.</strong> Nature 571: 279-283, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31168089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31168089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31168089[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/s41586-019-1286-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31168089">Qi et al. (2019)</a> showed that 24,25-epoxycholesterol, which they identified as an endogenous ligand of PTCH1, can stimulate Hedgehog signaling in cells and can trigger G protein signaling via human Smoothened in vitro. <a href="#17" class="mim-tip-reference" title="Qi, X., Liu, H., Thompson, B., McDonald, J., Zhang, C., Li, X. <strong>Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi.</strong> Nature 571: 279-283, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31168089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31168089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31168089[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/s41586-019-1286-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31168089">Qi et al. (2019)</a> presented a cryoelectron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein (see <a href="/entry/139310">139310</a>). The structure revealed a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class A GPCR-Gi complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31168089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Carcinoma</em></strong></p><p>
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Basal cell carcinomas are the commonest human cancer. Insight into their genesis came from identification of mutations in the Patched gene in patients with the basal cell nevus syndrome, a hereditary disease characterized by multiple basal cell carcinomas and by developmental abnormalities. The binding of Sonic hedgehog to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of smoothened (SMOH), a 7-transmembrane protein. According to this model, the inhibition of SMOH signaling is relieved following mutational inactivation of PTCH in basal cell nevus syndrome. <a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> identified activating somatic missense mutations in the SMOH gene itself in sporadic basal cell carcinomas from 3 patients. The mutant SMOH, unlike wildtype, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to basal cell carcinomas developed in transgenic murine skin overexpressing mutant SMOH. These findings support the role of SMOH as a signaling component of the SHH-receptor complex and provide direct evidence that mutated SMOH can function as an oncogene in basal cell carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Curry-Jones Syndrome</em></strong></p><p>
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In 8 patients with Curry-Jones syndrome (CRJS; <a href="/entry/601707">601707</a>), <a href="#28" class="mim-tip-reference" title="Twigg, S. R. F., Hufnagel, R. B., Miller, K. A., Zhou, Y., McGowan, S. J., Taylor, J., Craft, J., Taylor, J. C., Santoro, S. L., Huang, T., Hopkin, R. J., Brady, A. F., and 11 others. <strong>A recurrent mosaic mutation in SMO, encoding the Hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome.</strong> Am. J. Hum. Genet. 98: 1256-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27236920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27236920</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27236920[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27236920">Twigg et al. (2016)</a> identified somatic mosaicism in affected tissue samples for a missense mutation in the SMOH gene (L412F; <a href="#0003">601500.0003</a>). The authors noted that the same L412F mutation had previously been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and had been reported as the oncogenic driver in some of those tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27236920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Pallister-Hall-Like Syndrome</em></strong></p><p>
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In 2 brothers with hypothalamic hamartomas and polydactyly as well as various other skeletal and brain anomalies (PHLS; <a href="/entry/241800">241800</a>), <a href="#20" class="mim-tip-reference" title="Rubino, S., Qian, J., Pinheiro-Neto, C. D., Kenning, T. J., Adamo, M. A. <strong>A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases.</strong> J. Neurosurg. Pediat. 23: 98-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30497210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30497210</a>] [<a href="https://doi.org/10.3171/2018.7.PEDS18292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30497210">Rubino et al. (2018)</a> identified compound heterozygosity for a 2-bp deletion in the SMO gene (<a href="#0004">601500.0004</a>) and a deletion at chromosome 7q32.1 involving part of the SMO gene. The authors stated that this was the first report of a familial syndrome involving germline mutations in the SMO gene, and noted the variable expressivity between the 2 brothers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30497210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 7 patients from 5 families with Pallister-Hall-like syndrome, including the 2 brothers originally reported by <a href="#20" class="mim-tip-reference" title="Rubino, S., Qian, J., Pinheiro-Neto, C. D., Kenning, T. J., Adamo, M. A. <strong>A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases.</strong> J. Neurosurg. Pediat. 23: 98-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30497210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30497210</a>] [<a href="https://doi.org/10.3171/2018.7.PEDS18292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30497210">Rubino et al. (2018)</a>, <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> identified homozygous or compound heterozygous mutations in the SMO gene (<a href="#0004">601500.0004</a>-<a href="#0009">601500.0009</a>). Functional analysis demonstrated a loss-of-function mechanism with the SMO variants, resulting in alteration of the Hh pathway via instability of the protein, altered SMO trafficking to the primary cilium, or lack of SMO activation within the primary cilium. <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> noted that the patients displayed a broad spectrum of developmental anomalies, including postaxial polydactyly and hypothalamic hamartoma as well as other skeletal and brain anomalies, and congenital cardiac defects in some patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30497210+32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 gain insight into the role of SMO in hedgehog signaling in vertebrates, <a href="#33" class="mim-tip-reference" title="Zhang, X. M., Ramalho-Santos, M., McMahon, A. P. <strong>Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node.</strong> Cell 105: 781-792, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440720</a>]" pmid="11440720">Zhang et al. (2001)</a> generated a null allele of Smo by gene targeting in mouse embryonic stem (ES) cells. They showed that Smo acts epistatic to Ptc1 to mediate Shh and Ihh (<a href="/entry/600726">600726</a>) signaling in the early mouse embryo. Smo and Shh/Ihh compound mutants had identical phenotypes: embryos failed to turn, arresting at somite stages with a small, linear heart tube, an open gut, and cyclopia. The absence of visible left/right (L/R) asymmetry led the authors to examine the pathways controlling L/R situs. <a href="#33" class="mim-tip-reference" title="Zhang, X. M., Ramalho-Santos, M., McMahon, A. P. <strong>Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node.</strong> Cell 105: 781-792, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440720</a>]" pmid="11440720">Zhang et al. (2001)</a> presented evidence consistent with a model in which hedgehog signaling within the node is required for activation of GDF1 (<a href="/entry/602880">602880</a>) and induction of left-side determinants. Further, they demonstrated an absolute requirement for hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Wilbanks, A. M., Fralish, G. B., Kirby, M. L., Barak, L. S., Li, Y.-X., Caron, M. G. <strong>Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.</strong> Science 306: 2264-2267, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618520</a>] [<a href="https://doi.org/10.1126/science.1104193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15618520">Wilbanks et al. (2004)</a> showed that the functional knockdown of Arrb2 in zebrafish embryos recapitulates the many phenotypes of hedgehog pathway mutants. Expression of wildtype Arrb2, or constitutive activation of the hedgehog pathway downstream of Smo, rescues the phenotypes caused by Arrb2 deficiency. These results suggested to <a href="#30" class="mim-tip-reference" title="Wilbanks, A. M., Fralish, G. B., Kirby, M. L., Barak, L. S., Li, Y.-X., Caron, M. G. <strong>Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.</strong> Science 306: 2264-2267, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618520</a>] [<a href="https://doi.org/10.1126/science.1104193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15618520">Wilbanks et al. (2004)</a> that a functional interaction between Arrb2 and Smo may be critical to regulate hedgehog signaling in zebrafish development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15618520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 microarray analysis and in situ hybridization, <a href="#16" class="mim-tip-reference" title="Purcell, P., Joo, B. W., Hu, J. K., Tran, P. V., Calicchio, M. L., O'Connell, D. J., Maas, R. L., Tabin, C. J. <strong>Temporomandibular joint formation requires two distinct hedgehog-dependent steps.</strong> Proc. Nat. Acad. Sci. 106: 18297-18302, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815519</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815519[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.0908836106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19815519">Purcell et al. (2009)</a> showed that Smo was expressed during development of the temporomandibular joint (TMJ) in mice, with specific expression in the condyle and the disk. Mice with conditional deletion of Smo from chondrocyte progenitors formed a complete disk with morphology similar to wildtype, but the resulting structure failed to separate from the condyle. In contrast, mice lacking Gli2 (<a href="/entry/165230">165230</a>), another Hh signaling component expressed during TMJ development, exhibited missing TMJ disk and aberrant chondrogenic differentiation. The results suggested that Hh signaling is required at 2 distinct steps in TMJ disk formation: initiation of TMJ disk formation and disk-condyle separation after chondrogenic differentiation to form the lower joint cavity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19815519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Fish, E. W., Parnell, S. E., Sulik, K. K., Baker, L. K., Murdaugh, L. B., Lamson, D., Williams, K. P. <strong>Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL/6 mice.</strong> Birth Defects Res. 109: 49-54, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27801979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27801979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27801979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/bdra.23571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27801979">Fish et al. (2017)</a> injected pregnant C57BL/6J mice with Smoothened agonist (SAG) on gestational day (GD) 9.25, the time of limb bud injection, and examined embryos at GD 15. Preaxial polydactyly was the most frequently observed defect, and ranged from the addition of a thumb-like process to the addition of 2 complete fingers. When the thumb was affected, it was typically broadened, bifurcated, or duplicated. Whole-mount in situ hybridization revealed that SAG amplified the expression of Gli1 (<a href="/entry/165220">165220</a>) mRNA and, to a lesser extent, Gli2 (<a href="/entry/165230">165230</a>) mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27801979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 screen for recessive mutations affecting mouse embryonic neural development, <a href="#10" class="mim-tip-reference" title="Gigante, E. D., Long, A. B., Ben-Ami, J., Caspary, T. <strong>Hypomorphic Smo mutant with inefficient ciliary enrichment disrupts the highest level of vertebrate Hedgehog response.</strong> Dev. Biol. 437: 152-162, 2018. Note: Erratum: Dev. Biol. 450: 63 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29571613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29571613</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29571613[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ydbio.2018.03.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29571613">Gigante et al. (2018)</a> identified 'cabbie' (cbb), an asn223-to-lys (N223K) mutation in Smo. The mutation corresponded to N219K in human SMO and occurred within the linker domain, downstream of the CRD and immediately prior to transmembrane domain-1. The phenotype of cbb/cbb mice was less severe than that of Smo-null mice, suggesting that cbb was a hypomorphic allele of Smo. The highest level of Hh signaling was not achieved in cbb/cbb mice, leading to craniofacial and skeletal defects and abnormal neural tube patterning. Analysis with cbb/cbb mouse embryonic fibroblasts (MEFs) revealed that the N223K mutation disrupted full activation of Smo and impaired Shh signaling, as N223K disrupted the Smo ligand-binding pocket and binding of SAG to Smo. In ciliated cells, N223K mutant Smo was present, but at much lower levels than wildtype Smo, and consequently ciliated cells did not achieve the highest levels of Shh activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29571613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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</span>
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<strong>9 Selected Examples</a>):</strong>
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<a href="/allelicVariants/601500" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601500[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<a id="0001" class="mim-anchor"></a>
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<strong>.0001 BASAL CELL CARCINOMA, SOMATIC</strong>
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SMO, TRP535LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918347;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=rs121918347" 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=rs121918347" 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=RCV000008586" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008586" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008586</a>
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<p><a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> identified a trp535-to-leu (W535L) mutation in the seventh transmembrane domain of the SMOH protein in a sporadic basal cell carcinoma (see <a href="/entry/605462">605462</a>) from each of 2 patients. <a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> referred to this mutant SMOH as SMO-M2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0002" class="mim-anchor"></a>
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<strong>.0002 BASAL CELL CARCINOMA, SOMATIC</strong>
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SMO, ARG562GLN
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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> rs121918348 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918348;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/rs121918348?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=rs121918348" 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=rs121918348" 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=RCV000008587" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008587" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008587</a>
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<p><a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> identified an arg562-to-gln (R562Q) mutation in the C-terminal cytoplasmic tail of SMOH in a sporadic basal cell carcinoma (see <a href="/entry/605462">605462</a>). <a href="#31" class="mim-tip-reference" title="Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. <strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong> Nature 391: 90-92, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>] [<a href="https://doi.org/10.1038/34201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9422511">Xie et al. (1998)</a> referred to this mutation as SMO-M1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0003" class="mim-anchor"></a>
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<strong>.0003 CURRY-JONES SYNDROME, SOMATIC MOSAIC</strong>
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SMO, LEU412PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255280;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=rs879255280" 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=rs879255280" 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=RCV000236033" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000236033" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000236033</a>
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<p>In 8 patients with Curry-Jones syndrome (CRJS; <a href="/entry/601707">601707</a>), including the 2 patients originally reported by Curry and Jones (<a href="#4" class="mim-tip-reference" title="Cohen, M. M., Jr. <strong>Craniosynostosis update 1987.</strong> Am. J. Med. Genet. Suppl. 4: 99-148, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3144990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3144990</a>] [<a href="https://doi.org/10.1002/ajmg.1320310514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3144990">Cohen, 1988</a>) and 4 other patients previously reported by <a href="#25" class="mim-tip-reference" title="Temple, I. K., Eccles, D. M., Winter, R. M., Baraitser, M., Carr, S. B., Shortland, D., Jones, M. C., Curry, C. <strong>Craniofacial abnormalities, agenesis of the corpus callosum, polysyndactyly and abnormal skin and gut development: the Curry Jones syndrome.</strong> Clin. Dysmorph. 4: 116-129, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7606318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7606318</a>]" pmid="7606318">Temple et al. (1995)</a>, <a href="#27" class="mim-tip-reference" title="Thomas, E. R. A., Wakeling, E. L., Goodman, F. R., Dickinson, J. C., Hall, C. M., Brady, A. F. <strong>Mild case of Curry-Jones syndrome.</strong> Clin. Dysmorph. 15: 115-117, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16531740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16531740</a>] [<a href="https://doi.org/10.1097/01.mcd.0000194406.85052.de" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16531740">Thomas et al. (2006)</a>, and <a href="#11" class="mim-tip-reference" title="Grange, D. K., Clericuzio, C. L., Bayliss, S. J., Berk, D. R., Heideman, R. L., Higginson, J. K., Julian, S., Lind, A. <strong>Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the Sonic hedgehog-patched-GLI pathway.</strong> Am. J. Med. Genet. 146A: 2589-2597, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18798318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18798318</a>] [<a href="https://doi.org/10.1002/ajmg.a.32503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18798318">Grange et al. (2008)</a>, <a href="#28" class="mim-tip-reference" title="Twigg, S. R. F., Hufnagel, R. B., Miller, K. A., Zhou, Y., McGowan, S. J., Taylor, J., Craft, J., Taylor, J. C., Santoro, S. L., Huang, T., Hopkin, R. J., Brady, A. F., and 11 others. <strong>A recurrent mosaic mutation in SMO, encoding the Hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome.</strong> Am. J. Hum. Genet. 98: 1256-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27236920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27236920</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27236920[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27236920">Twigg et al. (2016)</a> identified somatic mosaicism in affected tissue samples for a c.1234C-T transition (c.1234C-T, NM_005631.4) in the SMOH gene, resulting in a leu412-to-phe (L412F) substitution in the transmembrane helix 5 within a pivot region. The mutant allele was present at levels substantially below 50% in the samples. Given the widespread mosaicism in these patients, the authors suggested that the mutation arises postzygotically early during embryonic development. <a href="#28" class="mim-tip-reference" title="Twigg, S. R. F., Hufnagel, R. B., Miller, K. A., Zhou, Y., McGowan, S. J., Taylor, J., Craft, J., Taylor, J. C., Santoro, S. L., Huang, T., Hopkin, R. J., Brady, A. F., and 11 others. <strong>A recurrent mosaic mutation in SMO, encoding the Hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome.</strong> Am. J. Hum. Genet. 98: 1256-1265, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27236920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27236920</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27236920[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27236920">Twigg et al. (2016)</a> noted that the L412F mutation had previously been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and had been reported as the oncogenic driver in some of those tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18798318+16531740+27236920+3144990+7606318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 PALLISTER-HALL-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1157132860 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1157132860;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=rs1157132860" 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=rs1157132860" 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=RCV001251439" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251439" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251439</a>
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<p>In 2 brothers with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>), <a href="#20" class="mim-tip-reference" title="Rubino, S., Qian, J., Pinheiro-Neto, C. D., Kenning, T. J., Adamo, M. A. <strong>A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases.</strong> J. Neurosurg. Pediat. 23: 98-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30497210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30497210</a>] [<a href="https://doi.org/10.3171/2018.7.PEDS18292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30497210">Rubino et al. (2018)</a> identified compound heterozygosity for a paternally inherited 2-bp deletion (c.2291_2292delAG) in the SMO gene, and a maternally inherited deletion at chromosome 7q32.1 that encompassed part of the SMO gene. The authors noted that apart from hypothalamic hamartomas and polydactyly, the brothers had different phenotypes, indicating variable expressivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30497210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> restudied the 2 brothers with PHLS (patients 2 and 3), originally reported by <a href="#20" class="mim-tip-reference" title="Rubino, S., Qian, J., Pinheiro-Neto, C. D., Kenning, T. J., Adamo, M. A. <strong>A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases.</strong> J. Neurosurg. Pediat. 23: 98-103, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30497210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30497210</a>] [<a href="https://doi.org/10.3171/2018.7.PEDS18292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30497210">Rubino et al. (2018)</a>, and noted that because the paternally inherited 2-bp deletion (c.2291_2292delAG, NM_005631.4) was located in the last exon of SMO, it would likely escape nonsense-mediated decay and result in a truncated protein (Gln764ArgfsTer52) lacking the highly conserved distal C-terminal tail. The mutation was not found in the gnomAD database. <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> analyzed patient DNA and determined the breakpoints of the maternally inherited 62-kb deletion (chr7:128,778,292_128,840,690del) and that the deletion encompassed exon 1 of SMO and all exons of the TSPAN33 gene (<a href="/entry/610120">610120</a>). RT-PCR of mRNA from patient fibroblasts showed a 50% reduction in SMO expression compared to controls. The authors quantified the expression of 2 Hedgehog (Hh; see <a href="/entry/600725">600725</a>) target genes, GLI1 (<a href="/entry/165220">165220</a>) and PTCH1 (<a href="/entry/601309">601309</a>), in stimulated fibroblasts from the 2 patients and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was undetectable within the PC in patient cells. Analysis of ciliary trafficking of GLI2 (<a href="/entry/165230">165230</a>), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30497210+32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PALLISTER-HALL-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs755698791 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs755698791;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/rs755698791?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=rs755698791" 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=rs755698791" 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=RCV001251440" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251440" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251440</a>
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<p>In a 3-year-old French boy (patient 1) with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>), <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> identified compound heterozygosity for a c.781C-T transition (c.781C-T, NM_005631.4) in the SMO gene, resulting in an arg261-to-cys (R261C) substitution at a residue within intracellular loop 1, and a c.1339G-T transversion in exon 7 resulting in a glu447-to-ter (E447X; <a href="#0006">601500.0006</a>) substitution. The nonsense mutation was not found in the gnomAD database, whereas the missense mutation was present at a very low minor allele frequency (1/121,411 alleles). Quantitative RT-PCR on mRNA from patient fibroblasts showed that SMO expression was 50% of that of age-matched controls, and cDNA sequencing confirmed that almost all of the patient mRNA carried the SMO missense allele. The authors quantified the expression of 2 Hedgehog (Hh; see <a href="/entry/600725">600725</a>) target genes, GLI1 (<a href="/entry/165220">165220</a>) and PTCH1 (<a href="/entry/601309">601309</a>), in stimulated fibroblasts from the patient and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was undetectable within the PC in patient cells. Analysis of ciliary trafficking of GLI2 (<a href="/entry/165230">165230</a>), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1006687669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1006687669;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/rs1006687669?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=rs1006687669" 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=rs1006687669" 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=RCV001251441" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251441" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251441</a>
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<p>For discussion of the c.1339G-T transversion (c.1339G-T, NM_005631.4) in the SMO gene, resulting in a glu447-to-ter (E447X) substitution, that was found in compound heterozygous state in a 3-year-old French boy (patient 1) with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>) by <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a>, see <a href="#0005">601500.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PALLISTER-HALL-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs767688088 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767688088;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/rs767688088?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=rs767688088" 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=rs767688088" 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=RCV001251443" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251443" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251443</a>
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<p>In a twin brother and sister (patients 6 and 7) with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>), <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> identified homozygosity for a c.1726C-T transition (c.1726C-T, NM_005631.4) in the SMO gene, resulting in an arg576-to-trp (R576W) substitution within the C-terminal cytoplasmic tail, which is required for SMO activation. Their consanguineous Dutch parents were heterozygous for the mutation. In an 8-year-old boy of West Indian ancestry (patient 5) with PHLS, the authors identified compound heterozygosity for the SMO R576W mutation and a c.1727G-A transition, resulting in an arg576-to-gln (R576Q; <a href="#0008">601500.0008</a>) substitution. His unaffected parents were each heterozygous for 1 of the mutations. Both mutations were found at very low minor allele frequency in the gnomAD database, only in heterozygosity (2/121,410 alleles and 1/251,186 alleles, respectively). All 3 patients exhibited preaxial polydactyly and atrioventricular septal defect, and the Dutch twins had additional cardiac anomalies whereas the West Indian boy had other skeletal anomalies. The authors quantified the expression of 2 Hedgehog (Hh; see <a href="/entry/600725">600725</a>) target genes, GLI1 (<a href="/entry/165220">165220</a>) and PTCH1 (<a href="/entry/601309">601309</a>), in stimulated fibroblasts from patients 6 and 7 and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was only partially translocated into the PC in patient cells. Analysis of ciliary trafficking of GLI2 (<a href="/entry/165230">165230</a>), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PALLISTER-HALL-LIKE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs577512487 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs577512487;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/rs577512487?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=rs577512487" 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=rs577512487" 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=RCV001251442" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251442" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251442</a>
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<p>For discussion of the c.1727G-A transition (c.1727G-A, NM_005631.4) in the SMO gene, resulting in an arg576-to-gln (R576Q) substitution, that was found in compound heterozygous state in an 8-year-old boy of West Indian ancestry (patient 5) with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>) by <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a>, see <a href="#0007">601500.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 PALLISTER-HALL-LIKE SYNDROME</strong>
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SMO, ILE429PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1793814652 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1793814652;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=rs1793814652" 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=rs1793814652" 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=RCV001251444" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001251444" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001251444</a>
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<p>In a 5-year-old boy (patient 4) with Pallister-Hall-like syndrome (PHLS; <a href="/entry/241800">241800</a>), <a href="#14" class="mim-tip-reference" title="Le, T.-L., Sribudiani, Y., Dong, X., Huber, C., Kois, C., Baujat, G., Gordon, C. T., Mayne, V., Galmiche, L., Serre, V., Goudin, N., Zarhrate, M., and 20 others. <strong>Bi-allelic variations of SMO in humans cause a broad spectrum of developmental anomalies due to abnormal hedgehog signaling.</strong> Am. J. Hum. Genet. 106: 779-792, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413283</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32413283[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.04.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413283">Le et al. (2020)</a> identified homozygosity for a c.1285A-T transversion (c.1285A-T, NM_005631.4) in the SMO gene, resulting in an ile429-to-phe (I429F) substitution. His first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. The authors quantified the expression of 2 Hedgehog (Hh; see <a href="/entry/600725">600725</a>) target genes, GLI1 (<a href="/entry/165220">165220</a>) and PTCH1 (<a href="/entry/601309">601309</a>), in stimulated fibroblasts from the patient and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was only partially translocated into the PC in patient cells. Analysis of ciliary trafficking of GLI2 (<a href="/entry/165230">165230</a>), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 href="https://doi.org/10.1002/bdra.23571" target="_blank">Full Text</a>]
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<a id="Teperino2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Teperino, R., Amann, S., Bayer, M., McGee, S. L., Loipetzberger, A., Connor, T., Jaeger, C., Kammerer, B., Winter, L., Wiche, G., Dalgaard, K., Selvaraj, M., and 9 others.
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<strong>Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat.</strong>
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Cell 151: 414-426, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23063129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23063129</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23063129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2012.09.021" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Thomas2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thomas, E. R. A., Wakeling, E. L., Goodman, F. R., Dickinson, J. C., Hall, C. M., Brady, A. F.
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<strong>Mild case of Curry-Jones syndrome.</strong>
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Clin. Dysmorph. 15: 115-117, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16531740/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16531740</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16531740" 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/10.1097/01.mcd.0000194406.85052.de" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Twigg2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Twigg, S. R. F., Hufnagel, R. B., Miller, K. A., Zhou, Y., McGowan, S. J., Taylor, J., Craft, J., Taylor, J. C., Santoro, S. L., Huang, T., Hopkin, R. J., Brady, A. F., and 11 others.
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<strong>A recurrent mosaic mutation in SMO, encoding the Hedgehog signal transducer smoothened, is the major cause of Curry-Jones syndrome.</strong>
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Am. J. Hum. Genet. 98: 1256-1265, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27236920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27236920</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27236920[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27236920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2016.04.007" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Wang2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, C., Wu, H., Katritch, V., Han, G. W., Huang, X.-P., Liu, W., Siu, F. Y., Roth, B. L., Cherezov, V., Stevens, R. C.
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<strong>Structure of the human smoothened receptor bound to an antitumour agent.</strong>
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Nature 497: 338-343, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23636324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23636324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23636324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23636324" 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/nature12167" 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="30" class="mim-anchor"></a>
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<a id="Wilbanks2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilbanks, A. M., Fralish, G. B., Kirby, M. L., Barak, L. S., Li, Y.-X., Caron, M. G.
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<strong>Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.</strong>
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Science 306: 2264-2267, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618520</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15618520" 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.1104193" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Xie1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J.
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<strong>Activating Smoothened mutations in sporadic basal-cell carcinoma.</strong>
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Nature 391: 90-92, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9422511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9422511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9422511" 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/10.1038/34201" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Yauch2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., Marshall, D., Fu, L., Januario, T., Kallop, D., Nannini-Pepe, M., Kotkow, K., Marsters, J. C., Jr., Rubin, L. L., de Sauvage, F. J.
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<strong>A paracrine requirement for hedgehog signalling in cancer.</strong>
|
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Nature 455: 406-410, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18754008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18754008</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18754008" 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/nature07275" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Zhang2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, X. M., Ramalho-Santos, M., McMahon, A. P.
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<strong>Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node.</strong>
|
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Cell 105: 781-792, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11440720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11440720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11440720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Zhao2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T.
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<strong>Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.</strong>
|
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Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19169242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19169242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19169242[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19169242" 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/nature07737" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="35" class="mim-anchor"></a>
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<a id="Zhao2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhao, Y., Tong, C., Jiang, J.
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<strong>Hedgehog regulates smoothened activity by inducing a conformational switch.</strong>
|
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Nature 450: 252-258, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17960137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17960137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17960137" 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/nature06225" target="_blank">Full Text</a>]
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</ol>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Bao Lige - updated : 12/13/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/07/2020<br>Ada Hamosh - updated : 05/22/2020<br>Ada Hamosh - updated : 05/22/2020<br>Ada Hamosh - updated : 10/04/2016<br>Marla J. F. O'Neill - updated : 07/20/2016<br>Ada Hamosh - updated : 01/30/2014<br>Ada Hamosh - updated : 8/27/2013<br>Ada Hamosh - updated : 8/27/2009<br>Ada Hamosh - updated : 4/28/2009<br>Ada Hamosh - updated : 2/18/2009<br>Ada Hamosh - updated : 10/2/2008<br>Ada Hamosh - updated : 7/17/2008<br>Ada Hamosh - updated : 1/9/2008<br>Paul J. Converse - updated : 11/9/2006<br>Ada Hamosh - updated : 11/21/2005<br>Ada Hamosh - updated : 3/3/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 9/13/2002<br>Stylianos E. Antonarakis - updated : 7/2/2001<br>Carol A. Bocchini - updated : 3/21/1999<br>Carol A. Bocchini - updated : 12/1/1998<br>Victor A. McKusick - updated : 9/30/1998<br>Moyra Smith - updated : 11/19/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Moyra Smith : 11/13/1996
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/16/2022
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 12/13/2021<br>carol : 08/10/2020<br>alopez : 08/07/2020<br>alopez : 05/22/2020<br>alopez : 05/22/2020<br>carol : 10/11/2019<br>alopez : 10/04/2016<br>carol : 07/28/2016<br>carol : 07/22/2016<br>carol : 07/20/2016<br>carol : 07/20/2016<br>alopez : 01/30/2014<br>alopez : 8/27/2013<br>alopez : 8/27/2013<br>carol : 4/22/2013<br>alopez : 9/8/2009<br>terry : 8/27/2009<br>alopez : 5/6/2009<br>terry : 4/28/2009<br>alopez : 2/20/2009<br>terry : 2/18/2009<br>alopez : 11/6/2008<br>terry : 10/8/2008<br>alopez : 10/6/2008<br>terry : 10/2/2008<br>alopez : 7/21/2008<br>terry : 7/17/2008<br>alopez : 1/28/2008<br>terry : 1/9/2008<br>mgross : 11/14/2006<br>terry : 11/9/2006<br>alopez : 11/21/2005<br>terry : 11/21/2005<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>alopez : 1/18/2005<br>alopez : 1/18/2005<br>terry : 1/14/2005<br>alopez : 9/13/2002<br>carol : 11/24/2001<br>mgross : 7/2/2001<br>alopez : 9/5/2000<br>terry : 3/22/1999<br>carol : 3/21/1999<br>terry : 12/2/1998<br>carol : 12/1/1998<br>carol : 10/5/1998<br>terry : 9/30/1998<br>alopez : 7/31/1998<br>dkim : 7/30/1998<br>mark : 1/6/1997<br>mark : 11/19/1996<br>mark : 11/14/1996<br>mark : 11/13/1996
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</span>
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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> 601500
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<div>
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<h3>
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<span class="mim-font">
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SMOOTHENED, FRIZZLED CLASS RECEPTOR; SMO
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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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<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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<h4>
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<span class="mim-font">
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SMOOTHENED, DROSOPHILA, HOMOLOG OF; SMOH
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMO</em></strong>
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</span>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q32.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:129,188,633-129,213,545 </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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7q32.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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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">
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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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Curry-Jones syndrome, somatic mosaic
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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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601707
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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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Pallister-Hall-like syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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241800
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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 recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>SMO is a positive effector of the SHH (600725) signaling pathway (summary by Purcell et al., 2009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stone et al. (1996) screened a rat embryonic library with the Drosophila 'Smoothened' (Smo) gene and isolated overlapping cDNA clones which encoded a protein of 794 amino acids. Subsequently they isolated a human homolog of the Drosophila Smo gene, which is 94% homologous to the rat gene. The rat and human SMO genes are 33% homologous to Drosophila Smo; in the putative transmembrane domains of the gene homology is 50%. Stone et al. (1996) reported that human and rat SMO appear to be 7-transmembrane G protein-coupled receptors with 4 glycosylation sites and a putative extracellular amino terminus 203-205 amino acids long which includes 13 cysteines and can bind a polypeptide ligand. They observed that the spatial distribution of the rat 'Patched' gene product PTC (601309) and SMO show considerable overlap in embryonic tissues. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Xie et al. (1998) reported that the SMO locus spans more than 35 kb of genomic DNA. They found that the SMO gene contains 12 exons within 24 kb of genomic DNA. Exons 1 and 2 contain 5-prime untranslated sequences, the initiation codon ATG, and the entire signal peptide. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization (FISH), Quirk et al. (1997) mapped the human SMO gene to 7q32. By the same method, Xie et al. (1998) mapped the gene to 7q31-q32. By FISH and radiation hybrid analysis, Sublett et al. (1998) refined the localization to 7q32.3. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stone et al. (1996) carried out competitor binding, crosslinking, and coprecipitation studies and demonstrated that there was no evidence that Smo acted as a receptor for Shh, the Sonic hedgehog gene product. They demonstrated that an epitope-tagged N-terminal Shh peptide binds specifically to mouse Ptc (601309). They also showed that Ptc and Smo form a complex to which Shh binds. Stone et al. (1996) noted that genetic mutations leading to a truncated or unstable Ptc protein are associated with the familial or sporadic form of basal cell carcinoma (BCC). This finding, combined with the fact that Ptc is a high-affinity binding protein for Shh, suggests that the hedgehog system may provide mitogenic or differentiative signals to basal cells in the skin throughout life. Stone et al. (1996) raised the possibility that BCNS (109400) and BCC might result from constitutive activation of SMO, which then 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 induce Smo activity. </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>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. 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>Jia et al. (2004) showed that PKA (see 188830) and casein kinase I (CKI; 600505) regulate Smo cell surface accumulation and activity in response to hedgehog (Hh; see Shh, 600725). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. Jia et al. (2004) showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, Jia et al. (2004) found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. Jia et al. (2004) concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity. </p><p>Corbit et al. (2005) showed that mammalian Smo is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Shh or activating mutations in Smo promoted ciliary localization, whereas the Smo antagonist cyclopamine inhibited ciliary localization. They showed that the translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain shown to be required for the ciliary localization of 7-transmembrane proteins in C. elegans. Mutation of this domain not only prevented ciliary localization but also eliminated Smo activity both in cultured cells and in zebrafish embryos. Thus, Corbit et al. (2005) concluded that Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium. </p><p>Using an assay for G protein activation sensitive for receptor-constitutive activity, Riobo et al. (2006) found that mouse Smo coupled with all members of the Gi family (see 139310), but not with members of other G protein families. Inhibitors of hedgehog signaling blocked coupling of Smo with Gi. In addition, Gi and the C-terminal tail of Smo were required for activation of Gli (165220). Riobo et al. (2006) proposed that SMO is the source of 2 signals, one operating through Gi and the other originating with the SMO C-terminal tail, that are required for activation of GLI. </p><p>Zhao et al. (2007) provided evidence that phosphorylation by hedgehog activates SMO by inducing a conformational switch in Drosophila melanogaster. This occurs by antagonizing multiple arg clusters in the SMO cytoplasmic tail. The arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. Hedgehog-induced phosphorylation disrupts the interaction and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. Zhao et al. (2007) found that increasing the number of mutations in the arg clusters progressively activated SMO. Zhao et al. (2007) concluded that by employing multiple arg clusters as inhibitory elements counteracted by differential phosphorylation, SMO acts as a rheostat to translate graded HH signals into distinct responses. </p><p>Kovacs et al. (2008) demonstrated that beta-arrestins mediate the activity-dependent interaction of SMO and the kinesin motor protein KIF3A (604683). This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. Beta-arrestin-1 (107940) or beta-arrestin-2 (107941) depletion prevented the localization of SMO to primary cilia and the SMO-dependent activation of GLI (165220). Kovacs et al. (2008) concluded that their results suggested roles for beta-arrestin in mediating the intracellular transport of a 7-transmembrane receptor to its obligate subcellular location for signaling. </p><p>Although a cell-autonomous role for hedgehog signaling (see 600725) in tumors had been described, Yauch et al. (2008) demonstrated that hedgehog ligands failed to activate signaling in tumor epithelial cells. In contrast, their data supported ligand-dependent activation of the hedgehog pathway in the stromal microenvironment. Specific inhibition of hedgehog signaling using small molecule inhibitors, a neutralizing anti-hedgehog antibody, or genetic deletion of Smo in the mouse stroma resulted in growth inhibition in xenograft tumor models. Yauch et al. (2008) concluded that their studies demonstrated a paracrine requirement for hedgehog ligand signaling in tumorigenesis of hedgehog-expressing cancers and have important implications for the development of hedgehog pathway antagonists in cancer. </p><p>Ogden et al. (2008) presented in vitro and in vivo evidence in Drosophila that Smoothened activates G-alpha-i (139310) to modulate intracellular cAMP levels in response to hedgehog. Ogden et al. (2008) concluded that Smoothened functions as a canonical G protein-coupled receptor, which signals through GNAI1 to regulate hedgehog pathway activation. </p><p>Zhao et al. (2009) demonstrated that the loss of Smo, an essential component of the hedgehog pathway, impairs hematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia (CML; 608232) by the BCR-ABL1 (see 151410) oncoprotein. Loss of Smo causes depletion of CML stem cells, which propagate the leukemia, whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, Zhao et al. (2009) showed that the cell fate determinant Numb (603728), which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacologic inhibition of hedgehog signaling impairs not only the propagation of CML driven by wildtype BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. Zhao et al. (2009) concluded that hedgehog pathway activity is required for maintenance of normal and neoplastic stem cells of the hematopoietic system and raised the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway. </p><p>Resistance of Bcr (151410)-Abl (189980)-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML; 608232) can cause relapse of disease and might be the origin for emerging drug-resistant clones. Dierks et al. (2008) identified Smo as a drug target in Bcr-Abl-positive LSCs. They showed that Hedgehog signaling is activated in LSCs through upregulation of Smo. While nullity for Smo does not affect long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacologic Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Dierks et al. (2008) postulated that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML. </p><p>Using a small molecule Smo agonist (SAG), Teperino et al. (2012) found that Hh signaling rapidly reprogrammed energy metabolism toward aerobic glycolysis in disparate mouse and human cell types. SAG rapidly activated the Smo-AMPK (see 602739) axis, which was dependent on the primary cilium and was compartmentalized at the cilium base. Treatment with Smo-selective partial agonists of Hh signaling uncoupled canonical and noncanonical Smo signaling and induced metabolic rewiring and acute glucose uptake both in vitro and in vivo. Furthermore, treatment with selective partial agonists drove robust insulin-independent glucose uptake in muscle and brown adipose tissue of mice, because Smo regulated metabolic flux, flexibility, and substrate specificity of exogenous ligand stimulation. </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 (600726), PTCH1 (601309), and SMO, 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>
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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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</div>
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<span class="mim-text-font">
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<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><strong><em>Crystal Structure</em></strong></p><p>
|
|
Wang et al. (2013) reported the crystal structure of the transmembrane domain of the human SMO receptor bound to a small molecule antagonist at 2.5-angstrom resolution. Although the SMO receptor shares the 7-transmembrane helical fold, most of the conserved motifs for class A G protein-coupled receptors (GPCRs) are absent, and the structure revealed an unusually complex arrangement of long extracellular loops stabilized by 4 disulfide bonds. The ligand binds at the extracellular end of the 7-transmembrane-helix bundle and forms extensive contacts with the loops. </p><p>Byrne et al. (2016) presented the crystal structures of the Hh signal transducer and oncoprotein Smoothened, a GPCR that contains 2 distinct ligand-binding sites: 1 in its transmembrane domain (TMD) and 1 in the cysteine-rich domain (CRD). The CRD is stacked atop the TMD, separated by an intervening wedge-like linker domain. Structure-guided mutations showed that the interface between the CRD, linker domain, and TMD stabilizes the inactive state of Smoothened. Unexpectedly, the authors found a cholesterol molecule bound to Smoothened in the CRD binding site. Mutations predicted to prevent cholesterol binding impaired the ability of Smoothened to transmit native Hh signals. Binding of a clinically used antagonist, vismodegib, to the TMD induced a conformational change that was propagated to the CRD, resulting in loss of cholesterol from the CRD-linker domain-TMD interface. Byrne et al. (2016) concluded that their results clarified the structural mechanism by which the activity of a GPCR is controlled by ligand-regulated interactions between its extracellular and transmembrane domains. </p><p>Deshpande et al. (2019) reported the crystal structure of active mouse Smo bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of Smo was associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models, a cholesterol molecule that is critical for Smo activation is bound deep within the 7-transmembrane pocket. Deshpande et al. (2019) proposed that the inactivation of PTCH1 (602309) by Hedgehog allows a transmembrane sterol to access this 7-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. Deshpande et al. (2019) concluded that their results, combined with signaling studies and molecular dynamics simulations, delineated the structural basis for PTCH1-SMO regulation, and suggested a strategy for overcoming clinical resistance to SMO inhibitors. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Qi et al. (2019) showed that 24,25-epoxycholesterol, which they identified as an endogenous ligand of PTCH1, can stimulate Hedgehog signaling in cells and can trigger G protein signaling via human Smoothened in vitro. Qi et al. (2019) presented a cryoelectron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein (see 139310). The structure revealed a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class A GPCR-Gi complexes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Basal Cell Carcinoma</em></strong></p><p>
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Basal cell carcinomas are the commonest human cancer. Insight into their genesis came from identification of mutations in the Patched gene in patients with the basal cell nevus syndrome, a hereditary disease characterized by multiple basal cell carcinomas and by developmental abnormalities. The binding of Sonic hedgehog to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of smoothened (SMOH), a 7-transmembrane protein. According to this model, the inhibition of SMOH signaling is relieved following mutational inactivation of PTCH in basal cell nevus syndrome. Xie et al. (1998) identified activating somatic missense mutations in the SMOH gene itself in sporadic basal cell carcinomas from 3 patients. The mutant SMOH, unlike wildtype, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to basal cell carcinomas developed in transgenic murine skin overexpressing mutant SMOH. These findings support the role of SMOH as a signaling component of the SHH-receptor complex and provide direct evidence that mutated SMOH can function as an oncogene in basal cell carcinomas. </p><p><strong><em>Curry-Jones Syndrome</em></strong></p><p>
|
|
In 8 patients with Curry-Jones syndrome (CRJS; 601707), Twigg et al. (2016) identified somatic mosaicism in affected tissue samples for a missense mutation in the SMOH gene (L412F; 601500.0003). The authors noted that the same L412F mutation had previously been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and had been reported as the oncogenic driver in some of those tumors. </p><p><strong><em>Pallister-Hall-Like Syndrome</em></strong></p><p>
|
|
In 2 brothers with hypothalamic hamartomas and polydactyly as well as various other skeletal and brain anomalies (PHLS; 241800), Rubino et al. (2018) identified compound heterozygosity for a 2-bp deletion in the SMO gene (601500.0004) and a deletion at chromosome 7q32.1 involving part of the SMO gene. The authors stated that this was the first report of a familial syndrome involving germline mutations in the SMO gene, and noted the variable expressivity between the 2 brothers. </p><p>In 7 patients from 5 families with Pallister-Hall-like syndrome, including the 2 brothers originally reported by Rubino et al. (2018), Le et al. (2020) identified homozygous or compound heterozygous mutations in the SMO gene (601500.0004-601500.0009). Functional analysis demonstrated a loss-of-function mechanism with the SMO variants, resulting in alteration of the Hh pathway via instability of the protein, altered SMO trafficking to the primary cilium, or lack of SMO activation within the primary cilium. Le et al. (2020) noted that the patients displayed a broad spectrum of developmental anomalies, including postaxial polydactyly and hypothalamic hamartoma as well as other skeletal and brain anomalies, and congenital cardiac defects in some patients. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To gain insight into the role of SMO in hedgehog signaling in vertebrates, Zhang et al. (2001) generated a null allele of Smo by gene targeting in mouse embryonic stem (ES) cells. They showed that Smo acts epistatic to Ptc1 to mediate Shh and Ihh (600726) signaling in the early mouse embryo. Smo and Shh/Ihh compound mutants had identical phenotypes: embryos failed to turn, arresting at somite stages with a small, linear heart tube, an open gut, and cyclopia. The absence of visible left/right (L/R) asymmetry led the authors to examine the pathways controlling L/R situs. Zhang et al. (2001) presented evidence consistent with a model in which hedgehog signaling within the node is required for activation of GDF1 (602880) and induction of left-side determinants. Further, they demonstrated an absolute requirement for hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis. </p><p>Wilbanks et al. (2004) showed that the functional knockdown of Arrb2 in zebrafish embryos recapitulates the many phenotypes of hedgehog pathway mutants. Expression of wildtype Arrb2, or constitutive activation of the hedgehog pathway downstream of Smo, rescues the phenotypes caused by Arrb2 deficiency. These results suggested to Wilbanks et al. (2004) that a functional interaction between Arrb2 and Smo may be critical to regulate hedgehog signaling in zebrafish development. </p><p>Using microarray analysis and in situ hybridization, Purcell et al. (2009) showed that Smo was expressed during development of the temporomandibular joint (TMJ) in mice, with specific expression in the condyle and the disk. Mice with conditional deletion of Smo from chondrocyte progenitors formed a complete disk with morphology similar to wildtype, but the resulting structure failed to separate from the condyle. In contrast, mice lacking Gli2 (165230), another Hh signaling component expressed during TMJ development, exhibited missing TMJ disk and aberrant chondrogenic differentiation. The results suggested that Hh signaling is required at 2 distinct steps in TMJ disk formation: initiation of TMJ disk formation and disk-condyle separation after chondrogenic differentiation to form the lower joint cavity. </p><p>Fish et al. (2017) injected pregnant C57BL/6J mice with Smoothened agonist (SAG) on gestational day (GD) 9.25, the time of limb bud injection, and examined embryos at GD 15. Preaxial polydactyly was the most frequently observed defect, and ranged from the addition of a thumb-like process to the addition of 2 complete fingers. When the thumb was affected, it was typically broadened, bifurcated, or duplicated. Whole-mount in situ hybridization revealed that SAG amplified the expression of Gli1 (165220) mRNA and, to a lesser extent, Gli2 (165230) mRNA. </p><p>In a screen for recessive mutations affecting mouse embryonic neural development, Gigante et al. (2018) identified 'cabbie' (cbb), an asn223-to-lys (N223K) mutation in Smo. The mutation corresponded to N219K in human SMO and occurred within the linker domain, downstream of the CRD and immediately prior to transmembrane domain-1. The phenotype of cbb/cbb mice was less severe than that of Smo-null mice, suggesting that cbb was a hypomorphic allele of Smo. The highest level of Hh signaling was not achieved in cbb/cbb mice, leading to craniofacial and skeletal defects and abnormal neural tube patterning. Analysis with cbb/cbb mouse embryonic fibroblasts (MEFs) revealed that the N223K mutation disrupted full activation of Smo and impaired Shh signaling, as N223K disrupted the Smo ligand-binding pocket and binding of SAG to Smo. In ciliated cells, N223K mutant Smo was present, but at much lower levels than wildtype Smo, and consequently ciliated cells did not achieve the highest levels of Shh activity. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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 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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SMO, TRP535LEU
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<br />
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SNP: rs121918347,
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ClinVar: RCV000008586
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</span>
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<div>
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<span class="mim-text-font">
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<p>Xie et al. (1998) identified a trp535-to-leu (W535L) mutation in the seventh transmembrane domain of the SMOH protein in a sporadic basal cell carcinoma (see 605462) from each of 2 patients. Xie et al. (1998) referred to this mutant SMOH as SMO-M2. </p>
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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>.0002 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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SMO, ARG562GLN
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<br />
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SNP: rs121918348,
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gnomAD: rs121918348,
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ClinVar: RCV000008587
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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>Xie et al. (1998) identified an arg562-to-gln (R562Q) mutation in the C-terminal cytoplasmic tail of SMOH in a sporadic basal cell carcinoma (see 605462). Xie et al. (1998) referred to this mutation as SMO-M1. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CURRY-JONES SYNDROME, SOMATIC MOSAIC</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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SMO, LEU412PHE
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<br />
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SNP: rs879255280,
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ClinVar: RCV000236033
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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 8 patients with Curry-Jones syndrome (CRJS; 601707), including the 2 patients originally reported by Curry and Jones (Cohen, 1988) and 4 other patients previously reported by Temple et al. (1995), Thomas et al. (2006), and Grange et al. (2008), Twigg et al. (2016) identified somatic mosaicism in affected tissue samples for a c.1234C-T transition (c.1234C-T, NM_005631.4) in the SMOH gene, resulting in a leu412-to-phe (L412F) substitution in the transmembrane helix 5 within a pivot region. The mutant allele was present at levels substantially below 50% in the samples. Given the widespread mosaicism in these patients, the authors suggested that the mutation arises postzygotically early during embryonic development. Twigg et al. (2016) noted that the L412F mutation had previously been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and had been reported as the oncogenic driver in some of those tumors. </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 PALLISTER-HALL-LIKE SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMO, 2-BP DEL, 2291AG
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<br />
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SNP: rs1157132860,
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ClinVar: RCV001251439
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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 brothers with Pallister-Hall-like syndrome (PHLS; 241800), Rubino et al. (2018) identified compound heterozygosity for a paternally inherited 2-bp deletion (c.2291_2292delAG) in the SMO gene, and a maternally inherited deletion at chromosome 7q32.1 that encompassed part of the SMO gene. The authors noted that apart from hypothalamic hamartomas and polydactyly, the brothers had different phenotypes, indicating variable expressivity. </p><p>Le et al. (2020) restudied the 2 brothers with PHLS (patients 2 and 3), originally reported by Rubino et al. (2018), and noted that because the paternally inherited 2-bp deletion (c.2291_2292delAG, NM_005631.4) was located in the last exon of SMO, it would likely escape nonsense-mediated decay and result in a truncated protein (Gln764ArgfsTer52) lacking the highly conserved distal C-terminal tail. The mutation was not found in the gnomAD database. Le et al. (2020) analyzed patient DNA and determined the breakpoints of the maternally inherited 62-kb deletion (chr7:128,778,292_128,840,690del) and that the deletion encompassed exon 1 of SMO and all exons of the TSPAN33 gene (610120). RT-PCR of mRNA from patient fibroblasts showed a 50% reduction in SMO expression compared to controls. The authors quantified the expression of 2 Hedgehog (Hh; see 600725) target genes, GLI1 (165220) and PTCH1 (601309), in stimulated fibroblasts from the 2 patients and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was undetectable within the PC in patient cells. Analysis of ciliary trafficking of GLI2 (165230), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 PALLISTER-HALL-LIKE SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMO, ARG261CYS
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<br />
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SNP: rs755698791,
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gnomAD: rs755698791,
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ClinVar: RCV001251440
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 3-year-old French boy (patient 1) with Pallister-Hall-like syndrome (PHLS; 241800), Le et al. (2020) identified compound heterozygosity for a c.781C-T transition (c.781C-T, NM_005631.4) in the SMO gene, resulting in an arg261-to-cys (R261C) substitution at a residue within intracellular loop 1, and a c.1339G-T transversion in exon 7 resulting in a glu447-to-ter (E447X; 601500.0006) substitution. The nonsense mutation was not found in the gnomAD database, whereas the missense mutation was present at a very low minor allele frequency (1/121,411 alleles). Quantitative RT-PCR on mRNA from patient fibroblasts showed that SMO expression was 50% of that of age-matched controls, and cDNA sequencing confirmed that almost all of the patient mRNA carried the SMO missense allele. The authors quantified the expression of 2 Hedgehog (Hh; see 600725) target genes, GLI1 (165220) and PTCH1 (601309), in stimulated fibroblasts from the patient and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was undetectable within the PC in patient cells. Analysis of ciliary trafficking of GLI2 (165230), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PALLISTER-HALL-LIKE SYNDROME</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
SMO, GLU447TER
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|
<br />
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SNP: rs1006687669,
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|
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gnomAD: rs1006687669,
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ClinVar: RCV001251441
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1339G-T transversion (c.1339G-T, NM_005631.4) in the SMO gene, resulting in a glu447-to-ter (E447X) substitution, that was found in compound heterozygous state in a 3-year-old French boy (patient 1) with Pallister-Hall-like syndrome (PHLS; 241800) by Le et al. (2020), see 601500.0005. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PALLISTER-HALL-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMO, ARG576TRP
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<br />
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|
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SNP: rs767688088,
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|
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gnomAD: rs767688088,
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ClinVar: RCV001251443
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a twin brother and sister (patients 6 and 7) with Pallister-Hall-like syndrome (PHLS; 241800), Le et al. (2020) identified homozygosity for a c.1726C-T transition (c.1726C-T, NM_005631.4) in the SMO gene, resulting in an arg576-to-trp (R576W) substitution within the C-terminal cytoplasmic tail, which is required for SMO activation. Their consanguineous Dutch parents were heterozygous for the mutation. In an 8-year-old boy of West Indian ancestry (patient 5) with PHLS, the authors identified compound heterozygosity for the SMO R576W mutation and a c.1727G-A transition, resulting in an arg576-to-gln (R576Q; 601500.0008) substitution. His unaffected parents were each heterozygous for 1 of the mutations. Both mutations were found at very low minor allele frequency in the gnomAD database, only in heterozygosity (2/121,410 alleles and 1/251,186 alleles, respectively). All 3 patients exhibited preaxial polydactyly and atrioventricular septal defect, and the Dutch twins had additional cardiac anomalies whereas the West Indian boy had other skeletal anomalies. The authors quantified the expression of 2 Hedgehog (Hh; see 600725) target genes, GLI1 (165220) and PTCH1 (601309), in stimulated fibroblasts from patients 6 and 7 and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was only partially translocated into the PC in patient cells. Analysis of ciliary trafficking of GLI2 (165230), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PALLISTER-HALL-LIKE SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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SMO, ARG576GLN
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<br />
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SNP: rs577512487,
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gnomAD: rs577512487,
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ClinVar: RCV001251442
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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>For discussion of the c.1727G-A transition (c.1727G-A, NM_005631.4) in the SMO gene, resulting in an arg576-to-gln (R576Q) substitution, that was found in compound heterozygous state in an 8-year-old boy of West Indian ancestry (patient 5) with Pallister-Hall-like syndrome (PHLS; 241800) by Le et al. (2020), see 601500.0007. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PALLISTER-HALL-LIKE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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SMO, ILE429PHE
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<br />
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SNP: rs1793814652,
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ClinVar: RCV001251444
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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 5-year-old boy (patient 4) with Pallister-Hall-like syndrome (PHLS; 241800), Le et al. (2020) identified homozygosity for a c.1285A-T transversion (c.1285A-T, NM_005631.4) in the SMO gene, resulting in an ile429-to-phe (I429F) substitution. His first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. The authors quantified the expression of 2 Hedgehog (Hh; see 600725) target genes, GLI1 (165220) and PTCH1 (601309), in stimulated fibroblasts from the patient and controls; in contrast to control cells, neither GLI1 nor PTCH1 expression was induced in patient cells, indicating a severe alteration of Hh pathway transduction. Control cells showed enrichment of SMO within the primary cilium (PC), whereas SMO was only partially translocated into the PC in patient cells. Analysis of ciliary trafficking of GLI2 (165230), the principal mediator of Hh-dependent transcriptional activation, showed accumulation at PC tips in both stimulated and unstimulated patient cells, indicating constitutive GLI2 localization to the PC when SMO is defective. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Byrne, E. F. X., Sircar, R., Miller, P. S., Hedger, G., Luchetti, G., Nachtergaele, S., Tully, M. D., Mydock-McGrane, L., Covey, D. F., Rambo, R. P., Sansom, M. S. P., Newstead, S., Rohatgi, R., Siebold, C.
|
|
<strong>Structural basis of Smoothened regulation by its extracellular domains.</strong>
|
|
Nature 535: 517-522, 2016.
|
|
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|
|
[PubMed: 27437577]
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[Full Text: https://doi.org/10.1038/nature18934]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Zhao, Y., Tong, C., Jiang, J.
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<strong>Hedgehog regulates smoothened activity by inducing a conformational switch.</strong>
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Nature 450: 252-258, 2007.
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[PubMed: 17960137]
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[Full Text: https://doi.org/10.1038/nature06225]
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Bao Lige - updated : 12/13/2021<br>Marla J. F. O'Neill - updated : 08/07/2020<br>Ada Hamosh - updated : 05/22/2020<br>Ada Hamosh - updated : 05/22/2020<br>Ada Hamosh - updated : 10/04/2016<br>Marla J. F. O'Neill - updated : 07/20/2016<br>Ada Hamosh - updated : 01/30/2014<br>Ada Hamosh - updated : 8/27/2013<br>Ada Hamosh - updated : 8/27/2009<br>Ada Hamosh - updated : 4/28/2009<br>Ada Hamosh - updated : 2/18/2009<br>Ada Hamosh - updated : 10/2/2008<br>Ada Hamosh - updated : 7/17/2008<br>Ada Hamosh - updated : 1/9/2008<br>Paul J. Converse - updated : 11/9/2006<br>Ada Hamosh - updated : 11/21/2005<br>Ada Hamosh - updated : 3/3/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 9/13/2002<br>Stylianos E. Antonarakis - updated : 7/2/2001<br>Carol A. Bocchini - updated : 3/21/1999<br>Carol A. Bocchini - updated : 12/1/1998<br>Victor A. McKusick - updated : 9/30/1998<br>Moyra Smith - updated : 11/19/1996
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Moyra Smith : 11/13/1996
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