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Entry
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- *165240 - GLI-KRUPPEL FAMILY MEMBER 3; GLI3
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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">*165240</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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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/165240">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>
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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>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000106571;t=ENST00000395925" 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=2737" 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=165240" 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 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=ENSG00000106571;t=ENST00000395925" 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_000168,XM_011515274,XM_017011997,XM_047420205,XM_047420206,XM_047420207,XM_047420208,XM_047420209" 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_000168" 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=165240" 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=01313&isoform_id=01313_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/GLI3" 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/183248,6102812,30142009,41393471,41393490,51094755,109658662,109731339,119393899,119614550,119614551,194387800,269849770,767945219,1034655001,2217366601,2217366603,2217366605,2217366607,2217366609,2462613725,2462613727,2462613729,2462613731,2462613733,2462613735,2462613737" 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/P10071" 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=2737" 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=ENSG00000106571;t=ENST00000395925" 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=GLI3" 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=GLI3" 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+2737" 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/GLI3" 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:2737" 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/2737" 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=ENST00000395925.8&hgg_start=41960949&hgg_end=42264268&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:4319" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=165240[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=165240[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/GLI3/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/ENSG00000106571" 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=GLI3" 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=GLI3" 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=GLI3" 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=GLI3&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/PA28722" 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:4319" 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/FBgn0004859.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:95729" 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/GLI3#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:95729" 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/2737/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=2737" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006604;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041111-162" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2737" 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=GLI3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 32985001, 56677004, 715707008<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
165240
|
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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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GLI-KRUPPEL FAMILY MEMBER 3; GLI3
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<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>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
ONCOGENE GLI3
|
|
</span>
|
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</h4>
|
|
</div>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GLI3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GLI3</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</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/7/211?start=-3&limit=10&highlight=211">7p14.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:41960949-42264268&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'})">7:41,960,949-42,264,268</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=175700,146510,174200,174700" 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="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/211?start=-3&limit=10&highlight=211">
|
|
7p14.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Greig cephalopolysyndactyly syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/175700"> 175700 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
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</tr>
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|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pallister-Hall syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/146510"> 146510 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
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<p>GLI3 encodes a zinc finger transcription factor that functions in the hedgehog (Hh; see SHH, <a href="/entry/600725">600725</a>) signal transduction pathway, which is dependent on primary cilia in many tissues. GLI3 undergoes posttranslational maturation into 2 isoforms with antagonistic transcriptional activities. SHH signaling causes proteolytic processing of GLI3 into a peptide, GLI3A, with transcriptional activator function. In the absence of SHH signaling, GLI3 is processed to a shorter peptide, GLI3R, with transcriptional repressor function. Processing of GLI3 to either form requires the primary cilium (summary by <a href="#27" class="mim-tip-reference" title="Laclef, C., Anselme, I., Besse, L., Catala, M., Palmyre, A., Baas, D., Paschaki, M., Pedraza, M., Metin, C., Durand, B., Schneider-Maunoury, S. <strong>The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.</strong> Hum. Molec. Genet. 24: 4997-5014, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26071364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26071364</a>] [<a href="https://doi.org/10.1093/hmg/ddv221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26071364">Laclef et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26071364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Like GLI2 (<a href="/entry/165230">165230</a>), the GLI3 gene was isolated by virtue of its cross-hybridization to the zinc finger gene GLI (<a href="/entry/165220">165220</a>), which is amplified in certain glioblastomas and represents a potential sequence-specific DNA-binding transcription factor from the GLI-Kruppel gene family. The GLI3 gene is expressed as an 8.5-kb mRNA in tissues such as testis, myometrium, placenta, and lung, and the protein product (relative molecular mass, 190,000) shows sequence-specific DNA binding (<a href="#41" class="mim-tip-reference" title="Ruppert, J. M., Kinzler, K. W., Wong, A. J., Bigner, S. H., Kao, F.-T., Law, M. L., Seuanez, H. N., O'Brien, S. J., Vogelstein, B. <strong>The GLI-Kruppel family of human genes.</strong> Molec. Cell. Biol. 8: 3104-3113, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2850480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2850480</a>] [<a href="https://doi.org/10.1128/mcb.8.8.3104-3113.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2850480">Ruppert et al., 1988</a>; <a href="#42" class="mim-tip-reference" title="Ruppert, J. M., Vogelstein, B., Arheden, K., Kinzler, K. W. <strong>GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity.</strong> Molec. Cell. Biol. 10: 5408-5415, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2118997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2118997</a>] [<a href="https://doi.org/10.1128/mcb.10.10.5408-5415.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2118997">Ruppert et al., 1990</a>). The gene encodes a predicted 1,596-amino acid polypeptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2118997+2850480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#53" class="mim-tip-reference" title="Vortkamp, A., Gessler, M., Le Paslier, D., Elaswarapu, R., Smith, S., Grzeschik, K.-H. <strong>Isolation of a yeast artificial chromosome contig spanning the Greig cephalopolysyndactyly syndrome (GCPS) gene region.</strong> Genomics 22: 563-568, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001967</a>] [<a href="https://doi.org/10.1006/geno.1994.1429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001967">Vortkamp et al. (1994)</a> isolated a YAC contig of more than 1,000 kb, including the GLI3 gene. In this contig the gene itself spanned at least 200 to 250 kb. A CpG island was located in the vicinity of the 5-prime region of the GLI3 cDNA, implying a potential promoter region. <a href="#25" class="mim-tip-reference" title="Kang, S., Rosenberg, M., Ko, V. D., Biesecker, L. G. <strong>Gene structure and allelic expression assay of the human GLI3 gene.</strong> Hum. Genet. 101: 154-157, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402960</a>] [<a href="https://doi.org/10.1007/s004390050605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9402960">Kang et al. (1997)</a> demonstrated that the coding region of GLI3 is composed of 14 exons, including a large exon of more than 2,500 bp. In addition, the gene contains 2 intragenic dinucleotide repeats, and 4 single-basepair polymorphisms in the coding region. <a href="#25" class="mim-tip-reference" title="Kang, S., Rosenberg, M., Ko, V. D., Biesecker, L. G. <strong>Gene structure and allelic expression assay of the human GLI3 gene.</strong> Hum. Genet. 101: 154-157, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9402960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9402960</a>] [<a href="https://doi.org/10.1007/s004390050605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9402960">Kang et al. (1997)</a> used these coding region polymorphisms to design an allele-specific expression study useful for investigating patients with Greig syndrome (GCPS; <a href="/entry/175700">175700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9402960+8001967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Wild, A., Kalff-Suske, M., Vortkamp, A., Bornholdt, D., Konig, R., Grzeschik, K.-H. <strong>Point mutations in human GLI3 cause Greig syndrome.</strong> Hum. Molec. Genet. 6: 1979-1984, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302279</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302279">Wild et al. (1997)</a> stated that the GLI3 gene contains 15 exons spanning 240 kb. The zinc finger domain is contained within 4 exons (10 through 13). Exon 1 is untranslated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420474[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/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> showed that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. <a href="#32" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420474[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/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> used genome editing to create 23 mouse deletion lines and intercrosses, including both single and combinatorial enhancer deletions at 7 distinct loci required for limb development including Gli3, Shox2 (<a href="/entry/602504">602504</a>), Tbx3 (<a href="/entry/601621">601621</a>), Tbx5 (<a href="/entry/601620">601620</a>), and Lhx5 (<a href="/entry/605992">605992</a>). Unexpectedly, none of the 10 deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of 3 representative developmental structures (limb, brain, and heart) uncovered more than 1,000 cases in which 5 or more enhancers with redundant activity patterns were found near the same gene. <a href="#32" class="mim-tip-reference" title="Osterwalder, M., Barozzi, I., Tissieres, V., Fukuda-Yuzawa, Y., Mannion, B. J., Afzal, S. Y., Lee, E. A., Zhu, Y., Plajzer-Frick, I., Pickle, C. S., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Akiyama, J. A., Afzal, V., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A. <strong>Enhancer redundancy provides phenotypic robustness in mammalian development.</strong> Nature 554: 239-243, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420474[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/nature25461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420474">Osterwalder et al. (2018)</a> concluded that their data indicated that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29420474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#41" class="mim-tip-reference" title="Ruppert, J. M., Kinzler, K. W., Wong, A. J., Bigner, S. H., Kao, F.-T., Law, M. L., Seuanez, H. N., O'Brien, S. J., Vogelstein, B. <strong>The GLI-Kruppel family of human genes.</strong> Molec. Cell. Biol. 8: 3104-3113, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2850480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2850480</a>] [<a href="https://doi.org/10.1128/mcb.8.8.3104-3113.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2850480">Ruppert et al. (1988)</a> mapped the GLI3 gene to chromosome 7 by analysis of DNA from human-rodent hybrid panels. Using in situ hybridization, <a href="#42" class="mim-tip-reference" title="Ruppert, J. M., Vogelstein, B., Arheden, K., Kinzler, K. W. <strong>GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity.</strong> Molec. Cell. Biol. 10: 5408-5415, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2118997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2118997</a>] [<a href="https://doi.org/10.1128/mcb.10.10.5408-5415.1990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2118997">Ruppert et al. (1990)</a> mapped the GLI3 gene to chromosome 7p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2118997+2850480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Although GLI1, located on 12q13, has been associated with glioma, GLI3 has not been related to glioma or other form of neoplasia (<a href="#51" class="mim-tip-reference" title="Vogelstein, B. <strong>Personal Communication.</strong> Baltimore, Md. 5/9/1994."None>Vogelstein, 1994</a>).</p><p>For a review of the role of the GLI3 gene in limb development, see <a href="#20" class="mim-tip-reference" title="Johnson, R. L., Tabin, C. J. <strong>Molecular models for vertebrate limb development.</strong> Cell 90: 979-990, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9323126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9323126</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80364-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9323126">Johnson and Tabin (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9323126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>GLI3 is homologous to the Drosophila cubitus interruptus (ci) gene product (Ci), which regulates the Patched (pct), gooseberry (gsb), and decapentaplegic (dpp) genes. Ci is sequestered in the cytoplasm and is subject to posttranslational processing whereby the full-length transcriptional activator form with 155 amino acids (Ci-155) can be cleaved to a repressor form with 75 amino acids (Ci-75). Under hedgehog (see <a href="/entry/600725">600725</a>) signaling, Ci-155 translocates to the nucleus, whereas in the absence of hedgehog, Ci-75 translocates to the nucleus. Based on the correlation of GLI3 truncation mutations and the human phenotypes, <a href="#44" class="mim-tip-reference" title="Shin, S. H., Kogerman, P., Lindstrom, E., Toftgard, R., Biesecker, L. G. <strong>GLI3 mutations in human disorders mimic Drosophila Cubitus interruptus protein functions and localization.</strong> Proc. Nat. Acad. Sci. 96: 2880-2884, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077605">Shin et al. (1999)</a> hypothesized that GLI3 shows transcriptional activation or repression activity and subcellular localization similar to Ci. They showed that full-length GLI3 localizes to the cytoplasm and activates PTCH (<a href="/entry/601309">601309</a>) gene expression, which is similar to full-length Ci-155. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#55" class="mim-tip-reference" title="Wang, B., Fallon, J. F., Beachy, P. A. <strong>Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.</strong> Cell 100: 423-434, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10693759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10693759</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80678-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10693759">Wang et al. (2000)</a> demonstrated that PKA (see <a href="/entry/176911">176911</a>)-dependent processing of vertebrate GLI3 in developing limb generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized SHH. They concluded that the resulting anterior/posterior GLI3 repressor gradient can be perturbed by mutations of the GLI3 gene in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid-2, producing a range of limb patterning malformations. The high relative abundance and potency of GLI3 repressor suggested specialization of GLI3 and its products for negative hedgehog pathway regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10693759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#56" class="mim-tip-reference" title="Wang, B., Li, Y. <strong>Evidence for the direct involvement of beta-TrCP in Gli3 protein processing.</strong> Proc. Nat. Acad. Sci. 103: 33-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16371461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16371461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16371461[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.0509927103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16371461">Wang and Li (2006)</a> demonstrated that overexpression of BTRC (<a href="/entry/603482">603482</a>), the vertebrate homolog of Drosophila Slimb, resulted in an increase in GLI3 repressor, whereas RNA interference of BTRC blocked GLI3 processing. BTRC could bind directly to phosphorylated GLI3 in vitro and in vivo, suggesting that it acts downstream of PKA, GSK3 (see <a href="/entry/605004">605004</a>), and CK1 (<a href="/entry/600505">600505</a>) in the processing pathway. Coimmunoprecipitation and immunoblot studies showed that GLI3 protein is polyubiquitinated and that its processing depends on proteasome activity. The findings suggested that BTRC is required for GLI3 processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16371461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 knockdown and overexpression analyses, <a href="#39" class="mim-tip-reference" title="Renault, M. A., Roncalli, J., Tongers, J., Misener, S., Thorne, T., Jujo, K., Ito, A., Clarke, T., Fung, C., Millay, M., Kamide, C., Scarpelli, A., Klyachko, E., Losordo, D. W. <strong>The Hedgehog transcription factor Gli3 modulates angiogenesis.</strong> Circ. Res. 105: 818-826, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19729595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19729595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19729595[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/10.1161/CIRCRESAHA.109.206706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19729595">Renault et al. (2009)</a> showed that GLI3 regulated function and gene expression in human umbilical vein endothelial cells (HUVECs). GLI3 activated the AKT (<a href="/entry/164730">164730</a>) pathway and the MAPK-ERK1 (MAPK3; <a href="/entry/601795">601795</a>)/ERK2 (MAPK1; <a href="/entry/176948">176948</a>) pathway in HUVECs, and GLI3-induced endothelial cell migration was dependent on both AKT and MAPK-ERK1/ERK2 activation. However, luciferase reporter assays revealed that GLI3 overexpression did not modulate GLI-dependent transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19729595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Laclef, C., Anselme, I., Besse, L., Catala, M., Palmyre, A., Baas, D., Paschaki, M., Pedraza, M., Metin, C., Durand, B., Schneider-Maunoury, S. <strong>The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.</strong> Hum. Molec. Genet. 24: 4997-5014, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26071364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26071364</a>] [<a href="https://doi.org/10.1093/hmg/ddv221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26071364">Laclef et al. (2015)</a> found that deletion of the ciliopathy gene Rpgrip1l (<a href="/entry/610937">610937</a>) in mice caused abnormal corticoseptal boundary formation in medial telencephalon, leading to disturbed location of guidepost cells in dorsomedial telencephalon and agenesis of corpus callosum. Deletion of the ciliary transcription factor Rfx3 (<a href="/entry/601337">601337</a>) results in a similar, but less severe, phenotype in mouse embryos. In both cases, overexpression of a Gli3 mutant with premature termination at codon 699, resulting in production of only a short Gli3 protein functionally similar to Gli3r, rescued corpus callosum formation, guidepost organization, and midline patterning. However, expression of the Gli3 mutant did not rescue ventral telencephalic phenotypes in Rfx3 -/- or Rpgrip1l -/- mutants. <a href="#27" class="mim-tip-reference" title="Laclef, C., Anselme, I., Besse, L., Catala, M., Palmyre, A., Baas, D., Paschaki, M., Pedraza, M., Metin, C., Durand, B., Schneider-Maunoury, S. <strong>The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.</strong> Hum. Molec. Genet. 24: 4997-5014, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26071364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26071364</a>] [<a href="https://doi.org/10.1093/hmg/ddv221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26071364">Laclef et al. (2015)</a> concluded that cilia are required for telencephalon patterning and that GLI3 has a major role in development of the corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26071364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Mastocytosis is a hematologic malignancy characterized by clonal accumulation of mast cells in 1 or more organs. A somatic mutation in KIT (<a href="/entry/164920">164920</a>), asp816 to val (D816V; <a href="/entry/164920#0009">164920.0009</a>), is present in about 85% of patients with mastocytosis. Using RT-PCR, immunofluorescence, and Western blot analyses, <a href="#35" class="mim-tip-reference" title="Polivka, L., Parietti, V., Bruneau, J., Soucie, E., Madrange, M., Bayard, E., Rignault, R., Canioni, D., Fraitag, S., Lhermitte, L., Feroul, M., Tissandier, M., and 18 others. <strong>The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis.</strong> Blood 138: 2396-2407, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34424959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34424959</a>] [<a href="https://doi.org/10.1182/blood.2020010207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34424959">Polivka et al. (2021)</a> showed that the Hh pathway was activated in neoplastic mast cells (MCs) from patients with mastocytosis and GCPS, and that the Hh signaling pathway cooperated with constitutively activate KIT in the onset of mastocytosis. Analysis with a GCPS mouse model revealed that mutated Gli3 synergized with the Kit D816V mutant to promote tumorigenicity, as Gli3 haploinsufficiency and high Gli3a/Gli3r ratio inhibited apoptosis and enhanced proliferation, especially when Kit was mutated. Analysis with HMC1.2 cells confirmed that Gli3 was a tumor suppressor, as expression of GLI3R drastically inhibited proliferation of HMC1.2 cells. Analysis with Hh antagonists confirmed that the Hh pathway was essential for MC transformation, and inhibition of the Hh pathway suppressed neoplastic MC proliferation in vitro and extended the survival time of mice with aggressive systemic mastocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34424959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Greig Cephalopolysyndactyly Syndrome</em></strong></p><p>
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<a href="#34" class="mim-tip-reference" title="Pettigrew, A. L., Greenberg, F., Caskey, C. T., Ledbetter, D. H. <strong>Greig syndrome associated with an interstitial deletion of 7p: confirmation of the localization of Greig syndrome to 7p13.</strong> Hum. Genet. 87: 452-456, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1879832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1879832</a>] [<a href="https://doi.org/10.1007/BF00197167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1879832">Pettigrew et al. (1991)</a> identified large deletions in the GLI3 gene in patients with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>) (see, e.g., <a href="#0001">165240.0001</a>). Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been found in association with GCPS (<a href="#34" class="mim-tip-reference" title="Pettigrew, A. L., Greenberg, F., Caskey, C. T., Ledbetter, D. H. <strong>Greig syndrome associated with an interstitial deletion of 7p: confirmation of the localization of Greig syndrome to 7p13.</strong> Hum. Genet. 87: 452-456, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1879832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1879832</a>] [<a href="https://doi.org/10.1007/BF00197167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1879832">Pettigrew et al., 1991</a>; <a href="#52" class="mim-tip-reference" title="Vortkamp, A., Gessler, M., Grzeschik, K.-H. <strong>GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families.</strong> Nature 352: 539-540, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1650914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1650914</a>] [<a href="https://doi.org/10.1038/352539a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1650914">Vortkamp et al., 1991</a>; <a href="#9" class="mim-tip-reference" title="Brueton, L., Huson, S. M., Winter, R. M., Williamson, R. <strong>Chromosomal localisation of a developmental gene in man: direct DNA analysis demonstrates that Greig cephalopolysyndactyly maps to 7p13.</strong> Am. J. Med. Genet. 31: 799-804, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3239571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3239571</a>] [<a href="https://doi.org/10.1002/ajmg.1320310412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3239571">Brueton et al., 1988</a>), although no mutations were identified in GCPS patients with normal karyotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3239571+1650914+1879832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 patients with GCPS, <a href="#57" class="mim-tip-reference" title="Wild, A., Kalff-Suske, M., Vortkamp, A., Bornholdt, D., Konig, R., Grzeschik, K.-H. <strong>Point mutations in human GLI3 cause Greig syndrome.</strong> Hum. Molec. Genet. 6: 1979-1984, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302279</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302279">Wild et al. (1997)</a> identified heterozygous point mutations in the GLI3 gene (<a href="#0018">165240.0018</a> and <a href="#0019">165240.0019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kalff-Suske, M., Wild, A., Topp, J., Wessling, M., Jacobsen, E.-M., Bornholdt, D., Engel, H., Heuer, H., Aalfs, C. M., Ausems, M. G. E. M., Barone, R., Herzog, A., and 11 others. <strong>Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.</strong> Hum. Molec. Genet. 8: 1769-1777, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441342</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441342">Kalff-Suske et al. (1999)</a> performed GLI3 mutation analysis on 24 GCPS patients. They identified 15 novel mutations (see, e.g., <a href="#0010">165240.0010</a>) present in heterozygous state in the patients' GLI3 alleles. The mutations mapped throughout the coding gene regions. Most were truncating mutations (9 of 15) that engendered prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. The 5 mutations identified within the protein regions C-terminal to the zinc fingers putatively affected additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to 2 adjacent independent domains in the C-terminal third of GLI3. Since these were the only functional domains affected by 3 C-terminally truncating mutations, <a href="#23" class="mim-tip-reference" title="Kalff-Suske, M., Wild, A., Topp, J., Wessling, M., Jacobsen, E.-M., Bornholdt, D., Engel, H., Heuer, H., Aalfs, C. M., Ausems, M. G. E. M., Barone, R., Herzog, A., and 11 others. <strong>Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.</strong> Hum. Molec. Genet. 8: 1769-1777, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441342</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441342">Kalff-Suske et al. (1999)</a> postulated that GCPS may be due either to the haploinsufficiency resulting from complete loss of 1 gene copy, or to functional haploinsufficiency related to compromised properties of this transcription factor, such as DNA binding and transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Biesecker, L. G. <strong>The Grieg polysyndactyly syndrome.</strong> Orphanet J. Rare Dis. 3: 10, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18435847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18435847</a>] [<a href="https://doi.org/10.1186/1750-1172-3-10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18435847">Biesecker (2008)</a> reviewed GCPS, noting the phenotypic overlap with acrocallosal syndrome (ACLS; <a href="/entry/200990">200990</a>). He remarked that in patients with substantial phenotypic overlap, molecular diagnostics are essential to arrive at a correct diagnosis; a mutation in GLI3 denotes GCPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18435847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Syndrome</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Kang, S., Graham, J. M., Jr., Olney, A. H., Biesecker, L. G. <strong>GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.</strong> Nature Genet. 15: 266-268, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054938</a>] [<a href="https://doi.org/10.1038/ng0397-266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054938">Kang et al. (1997)</a> identified frameshift mutations in the GLI3 gene (e.g., <a href="#0002">165240.0002</a>) in patients with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9054938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Numerous fragments of mitochondrial DNA migrated from the mitochondrial genome to the nuclear genome over evolutionary time (<a href="#54" class="mim-tip-reference" title="Wallace, D. C., Stugard, C., Murdock, D., Schurr, T., Brown, M. D. <strong>Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations.</strong> Proc. Nat. Acad. Sci. 94: 14900-14905, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9405711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9405711</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9405711[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.94.26.14900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9405711">Wallace et al., 1997</a>; <a href="#31" class="mim-tip-reference" title="Mourier, T., Hansen, A. J., Willerslev, E., Arctander, P. <strong>The Human Genome Project reveals a continuous transfer of large mitochondrial fragments to the nucleus. (Letter)</strong> Molec. Biol. Evol. 18: 1833-1837, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11504863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11504863</a>] [<a href="https://doi.org/10.1093/oxfordjournals.molbev.a003971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11504863">Mourier et al., 2001</a>; <a href="#49" class="mim-tip-reference" title="Tourmen, Y., Baris, O., Dessen, P., Jacques, C., Malthiery, Y., Reynier, P. <strong>Structure and chromosomal distribution of human mitochondrial pseudogenes.</strong> Genomics 80: 71-77, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12079285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12079285</a>] [<a href="https://doi.org/10.1006/geno.2002.6798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12079285">Tourmen et al., 2002</a>; <a href="#58" class="mim-tip-reference" title="Woischnik, M., Moraes, C. T. <strong>Pattern of organization of human mitochondrial pseudogenes in the nuclear genome.</strong> Genome Res. 12: 885-893, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12045142[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.227202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12045142">Woischnik and Moraes, 2002</a>). Mitochondrial DNA insertion polymorphisms can be used for human population studies (<a href="#48" class="mim-tip-reference" title="Thomas, R., Zischler, H., Paabo, S., Stoneking, M. <strong>Novel mitochondrial DNA insertion polymorphism and its usefulness for human population studies.</strong> Hum. Biol. 68: 847-854, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8979460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8979460</a>]" pmid="8979460">Thomas et al., 1996</a>). This process of mitochondria-to-nucleus DNA migration has the consequence that the extant mitochondrial proteome is now overwhelmingly encoded by the nuclear genome. <a href="#50" class="mim-tip-reference" title="Turner, C., Killoran, C., Thomas, N. S. T., Rosenberg, M., Chuzhanova, N. A., Johnston, J., Kemel, Y., Cooper, D. N., Biesecker, L. G. <strong>Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer.</strong> Hum. Genet. 112: 303-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545275</a>] [<a href="https://doi.org/10.1007/s00439-002-0892-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545275">Turner et al. (2003)</a> described a sporadic case of Pallister-Hall syndrome in which a de novo mitochondrial-nuclear translocation resulted in functional disruption of the GLI3 gene (<a href="#0011">165240.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12545275+8979460+12045142+12079285+9405711+11504863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Postaxial Polydactyly</em></strong></p><p>
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Postaxial polydactyly type A1 (PAPA1; <a href="/entry/174200">174200</a>) is an autosomal trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is usually functional, since it is well formed and articulates with the fifth or extrametacarpal/metatarsal. The gene responsible for this trait was mapped to the centromeric region of 7p by <a href="#36" class="mim-tip-reference" title="Radhakrishna, U., Blouin, J.-L., Mehenni, H., Patel, U. C., Patel, M. N., Solanki, J. V., Antonarakis, S. E. <strong>Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis.</strong> Am. J. Hum. Genet. 60: 597-604, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9042919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9042919</a>]" pmid="9042919">Radhakrishna et al. (1997)</a>. Since the GLI3 gene maps to the same region, <a href="#36" class="mim-tip-reference" title="Radhakrishna, U., Blouin, J.-L., Mehenni, H., Patel, U. C., Patel, M. N., Solanki, J. V., Antonarakis, S. E. <strong>Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis.</strong> Am. J. Hum. Genet. 60: 597-604, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9042919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9042919</a>]" pmid="9042919">Radhakrishna et al. (1997)</a> performed a mutation search in GLI3 cDNA from an Indian family with PAPA1 and demonstrated a mutation at codon 764 in 1 GLI3 allele. The mutation occurred 3-prime to the conserved domain termed Pzf1 (post zinc finger-1). Haploinsufficiency GLI3 is associated with some cases of GCPS, whereas frameshift mutations 3-prime to the zinc finger domains but upstream of the Pzf1 domain cause the Pallister-Hall syndrome. Thus, the coding of presumably different truncated GLI3 proteins are associated with different clinical syndromes, suggesting specific roles for the variant protein domains during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9042919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with postaxial polydactyly type B (PAPB; see <a href="/entry/174200">174200</a>) affecting both hands, <a href="#17" class="mim-tip-reference" title="Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. <strong>Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.</strong> Am. J. Med. Genet. 143A: 3150-3160, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000979</a>] [<a href="https://doi.org/10.1002/ajmg.a.32097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000979">Furniss et al. (2007)</a> identified a heterozygous 1-bp deletion (2372delC; <a href="#0015">165240.0015</a>) in the GLI3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation nonconsanguineous Saudi Arabian family with postaxial polydactyly, <a href="#1" class="mim-tip-reference" title="Al-Qattan, M. M. <strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong> Clin. Genet. 82: 502-504, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22428873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22428873</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01866.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22428873">Al-Qattan (2012)</a> identified heterozygosity for a 2-bp deletion (1615delGA; <a href="#0022">165240.0022</a>) in the GLI3 gene. <a href="#1" class="mim-tip-reference" title="Al-Qattan, M. M. <strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong> Clin. Genet. 82: 502-504, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22428873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22428873</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01866.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22428873">Al-Qattan (2012)</a> noted that although this frameshift predicts truncation in the N-terminal part of the gene and a GCPS phenotype would be expected, none of the family members had craniofacial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22428873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Preaxial Polydactyly Type IV</em></strong></p><p>
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In a large 4-generation family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV (PPD4; <a href="/entry/174700">174700</a>), <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> identified heterozygosity for a 1-bp insertion in the GLI3 gene (<a href="#0005">165240.0005</a>) that segregated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 father and son with PPD4, <a href="#15" class="mim-tip-reference" title="Fujioka, H., Ariga, T., Horiuchi, K., Otsu, M., Igawa, H., Kawashima, K., Yamamoto, Y., Sugihara, T., Sakiyama, Y. <strong>Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I.</strong> Clin. Genet. 67: 429-433, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811011</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00431.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811011">Fujioka et al. (2005)</a> identified heterozygosity for a nonsense mutation in the GLI3 gene (R290X; <a href="#0014">165240.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15811011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Somatic Mutations</em></strong></p><p>
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Approximately 5% of cases of hypothalamic hamartomas (HH; see <a href="/entry/241800">241800</a>) are associated with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>), which is caused by haploinsufficiency of GLI3. <a href="#10" class="mim-tip-reference" title="Craig, D. W., Itty, A., Panganiban, C., Szelinger, S., Kruer, M. C., Sekar, A., Reiman, D., Narayanan, V., Stephan, D. A., Kerrigan, J. F. <strong>Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus.</strong> Am. J. Hum. Genet. 82: 366-374, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252217</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252217[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.2007.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252217">Craig et al. (2008)</a> investigated the possibility that HH pathogenesis in sporadic cases is due to a somatic (tumor-only) mutation in GLI3. They isolated genomic DNA from peripheral blood and surgically resected HH tissue in 55 patients with sporadic HH and intractable epilepsy. A genomewide screen for loss of heterozygosity (LOH) and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue with Affymetrix 10K SNP microarrays. Additionally, resequencing and fine mapping with SNP genotyping were completed for the GLI3 gene with comparisons between peripheral blood and HH tissue pairs. By analyzing chromosomal copy number data for paired samples on the array, <a href="#10" class="mim-tip-reference" title="Craig, D. W., Itty, A., Panganiban, C., Szelinger, S., Kruer, M. C., Sekar, A., Reiman, D., Narayanan, V., Stephan, D. A., Kerrigan, J. F. <strong>Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus.</strong> Am. J. Hum. Genet. 82: 366-374, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252217</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252217[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.2007.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252217">Craig et al. (2008)</a> identified a somatic chromosomal abnormality on chromosome 7p in one HH tissue sample. Resequencing of GLI3 did not identify causative germline mutations but did identify LOH within the GLI3 gene in the HH tissue samples of 3 patients. Further genotyping of 28 SNPs within and surrounding GLI3 identified 5 additional patients exhibiting LOH. Together, these data provided evidence that the development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, nonsyndromic patients with HH and intractable epilepsy. Chromosomal abnormalities including the GLI3 locus were seen in 8 of 55 (15%) of the resected HH tissue samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="El Mouatani, A., Van Winckel, G., Zaafrane-Khachnaoui, K., Whalen, S., Achaiaa, A., Kaltenbach, S., Superti-Furga, A., Vekemans, M., Fodstad, H., Giuliano, F., Attie-Bitach, T. <strong>Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly.</strong> Am. J. Med. Genet. 185A: 3831-3837, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34296525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34296525</a>] [<a href="https://doi.org/10.1002/ajmg.a.62426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34296525">El Mouatani et al. (2021)</a> reported 3 unrelated patients with polydactyly, some with other features, and homozygous variants in the GLI3 gene. The first patient was a 10-year-old girl, born of first-cousin parents from Afghanistan, with bilateral postaxial polydactyly of the hands and dysmorphic facial features including flat face, hypertelorism, short philtrum, pointed chin, and microcephaly (-2 SD). She had global developmental delay and marked speech delay. She had craniosynostosis, conductive hearing loss, hyperopia and astigmatism, velar and submucosal cleft palate, bifid uvula, gingival growths, short tongue frenulum, oligodontia with short dysplastic teeth, and complete agenesis of the corpus callosum. A targeted 148 gene panel identified a homozygous missense variant in exon 5 (c.668G-A, NM_000168.5; S223N). Both parents were heterozygous for the variant and had no evidence of polydactyly. No functional evidence was provided. The variant was present in 4 of 251,214 alleles in only heterozygous state in the gnomAD database. The second patient was a 2-month-old male, born to first cousins of North African ancestry. Both parents had an unremarkable medical history, but on the mother's side there were relatives with polydactyly and on the father's side there were relatives with syndactyly and a neurodevelopmental disorder. The patient was born with bilateral polysyndactyly of hands and feet and a deviated, proximally placed thumb. He also had an epigastric and umbilical hernia. Brain MRI was unremarkable. Sanger sequencing of GLI3 exons and flanking intronic sequences identified a homozygous missense variant in exon 12 (c.1673C-T, NM_000168.5, S558L). Both parents were carriers. The variant was not present in the gnomAD database. No functional testing was performed, and no other genes were sequenced. The third patient was a 42-year-old man with bilateral mesoaxial polydactyly of the hands. He had a flat face, short philtrum, and a height of 1.61 m (-2 SD), severely impaired intellectual development, limited language, sensorineural hearing loss, strabismus, bilateral ptosis, ophthalmoplegia, short and large uvula, and short penis. Brain MRI showed hypoplastic corpus callosum, vermian atrophy (molar tooth sign), and retrocerebellar cyst. A targeted 96 gene panel showed homozygosity for a missense variant (c.565_567delinsTCT, NM_000168.5; P189S). His mother carried the variant, but his father was not available for testing. In the gnomAD database, the variant was present as 2 rare phased variants (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201940674;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs201940674</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371984494;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs371984494</a>) in only heterozygous state. No functional testing was performed. <a href="#19" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 1/31/2024."None>Hamosh (2024)</a> noted that in gnomAD on 1/31/24, the S223N variant was present 16 times; the S558L variant was present once; and the P189S variant was present 300 times for a highest population frequency of 0.00108 in the Ashkenazi Jewish population. She also noted that the P189S variant was labeled as likely benign by 2 groups in ClinVar (1/31/24). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34296525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#44" class="mim-tip-reference" title="Shin, S. H., Kogerman, P., Lindstrom, E., Toftgard, R., Biesecker, L. G. <strong>GLI3 mutations in human disorders mimic Drosophila Cubitus interruptus protein functions and localization.</strong> Proc. Nat. Acad. Sci. 96: 2880-2884, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077605</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077605[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077605">Shin et al. (1999)</a> found that the mutant GLI3 protein of the Pallister-Hall syndrome localizes to the nucleus and represses GLI3-activated PTCH expression, which is similar to Ci-75. The mutant protein of Greig cephalopolysyndactyly syndrome has no effect on GLI3-activated PTCH transcription, consistent with the role of haploinsufficiency in this disorder. The mutant GLI3 protein of type A1 postaxial polysyndactyly showed less specific subcellular localization but still inhibited GLI3-activated PTCH transcription, suggesting that it may be a weaker allele than the Pallister-Hall mutation. These data showed that GLI3 mutations in humans mimic the functional effects of the Drosophila ci gene and correlate with the distinct effects of these mutations on human development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kalff-Suske, M., Wild, A., Topp, J., Wessling, M., Jacobsen, E.-M., Bornholdt, D., Engel, H., Heuer, H., Aalfs, C. M., Ausems, M. G. E. M., Barone, R., Herzog, A., and 11 others. <strong>Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.</strong> Hum. Molec. Genet. 8: 1769-1777, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441342</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441342">Kalff-Suske et al. (1999)</a> provided a summary of known GLI3 mutations in GCPS, PHS, and PAPA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Up to 1999, mutations in the GLI3 gene had been identified in Greig cephalopolysyndactyly, Pallister-Hall syndrome, and postaxial polydactyly type A. <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> demonstrated a 1-nucleotide frameshift insertion (<a href="#0005">165240.0005</a>) resulting in a truncated protein of 1,245 amino acids in a family with preaxial polydactyly type IV (<a href="/entry/174700">174700</a>). They found a frameshift mutation due to a 1-nucleotide deletion (<a href="#0007">165240.0007</a>) in affected members of a family with dominant postaxial polydactyly type A/B (with type A and type B in the same family). In 2 other families with a mixed form of postaxial polydactyly, a nonsense mutation (R643X; <a href="#0008">165240.0008</a>) was found in one and a missense mutation (G727R; <a href="#0009">165240.0009</a>) in the other. A patient with Pallister-Hall syndrome had a nonsense mutation (E1147X; <a href="#0006">165240.0006</a>). These results added 2 phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. Phenotype could not be predicted from the position of the GLI3 mutations. <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> proposed that all phenotypes associated with GLI3 mutations be called 'GLI3 morphopathies,' since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., and 36 others. <strong>Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.</strong> Am. J. Hum. Genet. 76: 609-622, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15739154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15739154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15739154[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15739154">Johnston et al. (2005)</a> hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause Pallister-Hall syndrome, whereas haploinsufficiency of GLI3 causes Greig cephalopolysyndactyly syndrome. To test this hypothesis, they screened 46 patients with PHS and 89 patients with GCPS for GLI3 mutations. They detected 47 pathologic mutations (among 60 probands), and when these mutations were combined with previously published mutations, 2 genotype-phenotype correlations were evident. GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Among the frameshift/nonsense mutations, <a href="#21" class="mim-tip-reference" title="Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., and 36 others. <strong>Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.</strong> Am. J. Hum. Genet. 76: 609-622, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15739154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15739154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15739154[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15739154">Johnston et al. (2005)</a> found a clear genotype/phenotype correlation. Mutations in the first third of the gene (from open reading frame nucleotides 1-1997) caused GCPS, and mutations in the second third of the gene (from nucleotides 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3-prime third of the gene (after open reading frame nucleotide 3481), and no patients with PHS had mutations in this region. These results demonstrated a robust genotype/phenotype correlation for GLI3 mutations and strongly supported the hypothesis that these 2 allelic disorders have distinct modes of pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15739154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Biesecker, L. G. <strong>What you can learn from one gene: GLI3.</strong> J. Med. Genet. 43: 465-469, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740916[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2004.029181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16740916">Biesecker (2006)</a> reviewed 'what you can learn from one gene: GLI3.' He pointed out that the mutations in GLI3 that cause Pallister-Hall syndrome and those that cause Greig cephalopolysyndactyly correlate with the phenotypes on 2 levels: many types of inactivating mutations cause GCPS, whereas PHS is caused almost exclusively by truncation mutations in the middle third of the gene. This mutational correlation is supported by in vitro and animal model experimentation showing that the truncation mutations correlate with the posttranslational regulation of the gene, which is accomplished by proteolytic processing to give GLI3 both a transcriptional repressor and activator effect. Thus, GLI3 is a bifunctional transcriptional switch and these attributes correlate with the phenotype. The PHS and GCPS phenotypes caused by GLI3 mutations are qualitatively distinct but both encompass a wide range of severity that may include nonsyndromic polydactyly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16740916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Johnston, J. J., Sapp, J. C., Turner, J. T., Amor, D., Aftimos, S., Aleck, K. A., Bocian, M., Bodurtha, J. N., Cox, G. F., Curry, C. J., Day, R., Donnai, D., and 41 others. <strong>Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations.</strong> Hum. Mutat. 31: 1142-1154, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20672375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20672375</a>] [<a href="https://doi.org/10.1002/humu.21328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20672375">Johnston et al. (2010)</a> reported results from a cohort of 93 probands referred for GLI3 analysis: mutations were identified in 11 (65%) of 17 probands fulfilling criteria for GCPS, in 1 (50%) of 2 probands with PHS, in 8 (29%) of 28 probands with features overlapping GCPS, in 8 (40%) of 20 probands with features overlapping PHS, in 6 (29%) of 21 patients with features of orofaciodigital syndrome (OFD; see <a href="/entry/311200">311200</a>) in addition to 1 or more features of GCPS or PHS, and in 1 (20%) of 5 probands with isolated PAPA. <a href="#22" class="mim-tip-reference" title="Johnston, J. J., Sapp, J. C., Turner, J. T., Amor, D., Aftimos, S., Aleck, K. A., Bocian, M., Bodurtha, J. N., Cox, G. F., Curry, C. J., Day, R., Donnai, D., and 41 others. <strong>Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations.</strong> Hum. Mutat. 31: 1142-1154, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20672375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20672375</a>] [<a href="https://doi.org/10.1002/humu.21328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20672375">Johnston et al. (2010)</a> noted that the combination of these data with those of their previous work (<a href="#21" class="mim-tip-reference" title="Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., and 36 others. <strong>Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.</strong> Am. J. Hum. Genet. 76: 609-622, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15739154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15739154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15739154[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15739154">Johnston et al., 2005</a>) showed that patients manifesting features sufficient for clinical diagnosis of PHS or GCPS have a high chance of having a mutation in GLI3 (91% and 68%, respectively). The finding of GLI3 mutations in patients with features of OFD supported the observation that GLI3 interacts with cilia. <a href="#22" class="mim-tip-reference" title="Johnston, J. J., Sapp, J. C., Turner, J. T., Amor, D., Aftimos, S., Aleck, K. A., Bocian, M., Bodurtha, J. N., Cox, G. F., Curry, C. J., Day, R., Donnai, D., and 41 others. <strong>Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations.</strong> Hum. Mutat. 31: 1142-1154, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20672375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20672375</a>] [<a href="https://doi.org/10.1002/humu.21328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20672375">Johnston et al. (2010)</a> concluded that the phenotypic spectrum of GLI3 mutations was broader than that encompassed by the clinical diagnostic criteria, but that the genotype/phenotype correlation persisted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15739154+20672375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Demurger, F., Ichkou, A., Mougou-Zerelli, S., Le Merrer, M., Goudefroye, G., Delezoide, A.-L., Quelin, C., Manouvrier, S., Baujat, G., Fradin, M., Pasquier, L., Megarbane, A., and 40 others. <strong>New insights into genotype-phenotype correlation for GLI3 mutations.</strong> Europ. J. Hum. Genet. 23: 92-102, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24736735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24736735</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24736735[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.62" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24736735">Demurger et al. (2015)</a> reported the molecular and clinical results from their study of a cohort of 76 probands with either a GLI3 mutation (49 with GCPS and 21 with PHS) or a large deletion encompassing the GLI3 gene (6 with GCPS). Most (41) of the reported mutations were novel and supported previously reported genotype/phenotype correlations. Truncating mutations in the middle third of the gene generally resulted in PHS, whereas exonic deletions and missense and truncating mutations elsewhere in the gene caused GCPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24736735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#28" class="mim-tip-reference" title="Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F., Chiang, C. <strong>Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity.</strong> Nature 418: 979-983, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198547</a>] [<a href="https://doi.org/10.1038/nature01033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198547">Litingtung et al. (2002)</a> reported genetic analyses in mice showing that Shh and Gli3 are dispensable for formation of limb skeletal elements. The limbs of double-knockout Shh/Gli mice are distally complete and polydactylous, but completely lack wildtype digit identities. <a href="#28" class="mim-tip-reference" title="Litingtung, Y., Dahn, R. D., Li, Y., Fallon, J. F., Chiang, C. <strong>Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity.</strong> Nature 418: 979-983, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198547</a>] [<a href="https://doi.org/10.1038/nature01033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198547">Litingtung et al. (2002)</a> showed that the effects of Shh signaling on skeletal patterning and ridge maintenance are necessarily mediated through Gli3. The authors proposed that the function of Shh and Gli3 in limb skeletal patterning is limited to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification, by regulating the relative balance of Gli3 transcriptional activator and repressor activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12198547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="te Welscher, P., Zuniga, A., Kuijper, S., Drenth, T., Goedemans, H. J., Meijlink, F., Zeller, R. <strong>Progression of vertebrate limb development through SHH-mediated counteraction of GLI3.</strong> Science 298: 827-830, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215652</a>] [<a href="https://doi.org/10.1126/science.1075620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215652">Te Welscher et al. (2002)</a> reported that the polydactyly of Gli3-deficient mice arises independently of Shh signaling. Disruption of one or both Gli3 alleles in mouse embryos lacking Shh progressively restored limb distal development and digit formation. <a href="#47" class="mim-tip-reference" title="te Welscher, P., Zuniga, A., Kuijper, S., Drenth, T., Goedemans, H. J., Meijlink, F., Zeller, R. <strong>Progression of vertebrate limb development through SHH-mediated counteraction of GLI3.</strong> Science 298: 827-830, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215652</a>] [<a href="https://doi.org/10.1126/science.1075620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215652">Te Welscher et al. (2002)</a> concluded that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. The limbs of Gli3-deficient embryos were polydactylous, whereas 1 fused forearm bone and no digit arch formed in limbs of Shh-deficient embryos. Disruption of 1 Gli3 allele on an Shh-knockout background resulted in embryos with 2 forearm bones and rudimentary digits. The limbs of double homozygous mouse embryos were grossly morphologically indistinguishable from the limbs of Gli3 homozygous embryos. <a href="#47" class="mim-tip-reference" title="te Welscher, P., Zuniga, A., Kuijper, S., Drenth, T., Goedemans, H. J., Meijlink, F., Zeller, R. <strong>Progression of vertebrate limb development through SHH-mediated counteraction of GLI3.</strong> Science 298: 827-830, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215652</a>] [<a href="https://doi.org/10.1126/science.1075620" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215652">Te Welscher et al. (2002)</a> showed that, whereas the polydactyly of Gli3 -/- mice is Shh-independent, the polydactyly of Alx4 (<a href="/entry/605420">605420</a>) mutant mice depends on Shh signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12215652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Bose, J., Grotewold, L., Ruther, U. <strong>Pallister-Hall syndrome phenotype in mice mutant for Gli3.</strong> Hum. Molec. Genet. 11: 1129-1135, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978771</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978771">Bose et al. (2002)</a> produced transgenic mice homozygous for a mutation lying 3-prime to the zinc finger DNA-binding domain of Gli3. These mice, which died shortly after birth, exhibited central polydactyly as well as a wide range of developmental abnormalities encompassing almost all of the common PHS features, including imperforate anus; gastrointestinal, epiglottis, and larynx defects; abnormal kidney development; and absence of adrenal glands. TUNEL assays revealed a decrease in apoptosis within the interdigital webs of these animals, although MSX2 (<a href="/entry/123101">123101</a>) expression, which is also involved in this process, was apparently not affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Barna, M., Pandolfi, P. P., Niswander, L. <strong>Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. (Letter)</strong> Nature 436: 277-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015334</a>] [<a href="https://doi.org/10.1038/nature03801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16015334">Barna et al. (2005)</a> identified a genetic interaction between Gli3 and Plzf (<a href="/entry/176797">176797</a>) that is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot were relatively unperturbed in Gli3/Plzf double knockout mouse embryos. <a href="#3" class="mim-tip-reference" title="Barna, M., Pandolfi, P. P., Niswander, L. <strong>Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. (Letter)</strong> Nature 436: 277-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015334</a>] [<a href="https://doi.org/10.1038/nature03801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16015334">Barna et al. (2005)</a> demonstrated that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb bud independently of proximal-distal (P-D) patterning markers and overall limb bud size. Moreover, the limb defects in the double knockout embryos correlated with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor type 1B (Bmpr1b; <a href="/entry/603248">603248</a>) at the onset of limb development. <a href="#3" class="mim-tip-reference" title="Barna, M., Pandolfi, P. P., Niswander, L. <strong>Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. (Letter)</strong> Nature 436: 277-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015334</a>] [<a href="https://doi.org/10.1038/nature03801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16015334">Barna et al. (2005)</a> concluded that development of proximal and distal skeletal elements is distinctly regulated during early limb bud formation. The initial division of the vertebrate limb into 2 distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16015334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C., Baxter, L. L., Pavan, W. J. <strong>A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.</strong> Hum. Molec. Genet. 17: 2118-2131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18397875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18397875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18397875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18397875">Matera et al. (2008)</a> found that homozygosity for a null mutation of Gli3 (tyr350 to ter) in mice was embryonic lethal. Heterozygous mutant mice exhibited numerous skeletal defects, and a portion of them exhibited ventral hypopigmentation. Homozygous mutant embryos had a reduced number of early-stage melanoblasts. Neural crest cells from homozygous mutant embryos differentiated into highly pigmented melanocytes in culture, and skin from homozygous mutant mice produced pigment in skin grafts, suggesting that Gli3-deficient melanoblasts are able to terminally differentiate. Heterozygosity for the Gli3 mutation increased the penetrance and severity of the hypopigmentation phenotype of Sox10 (<a href="/entry/602229">602229</a>) +/- mice, a model for human Waardenburg syndrome (<a href="/entry/277580">277580</a>). A C-terminal truncation mutant of Gli3 that retained its transcriptional repressor function, but not the activator domain, was sufficient to induce melanoblast differentiation in mouse embryos. <a href="#29" class="mim-tip-reference" title="Matera, I., Watkins-Chow, D. E., Loftus, S. K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C., Baxter, L. L., Pavan, W. J. <strong>A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.</strong> Hum. Molec. Genet. 17: 2118-2131, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18397875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18397875</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18397875[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18397875">Matera et al. (2008)</a> concluded that the repressor function of GLI3 is required for melanoblast specification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18397875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR analysis, <a href="#39" class="mim-tip-reference" title="Renault, M. A., Roncalli, J., Tongers, J., Misener, S., Thorne, T., Jujo, K., Ito, A., Clarke, T., Fung, C., Millay, M., Kamide, C., Scarpelli, A., Klyachko, E., Losordo, D. W. <strong>The Hedgehog transcription factor Gli3 modulates angiogenesis.</strong> Circ. Res. 105: 818-826, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19729595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19729595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19729595[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/10.1161/CIRCRESAHA.109.206706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19729595">Renault et al. (2009)</a> confirmed that Gli3 +/- mice were haploinsufficient with significantly reduced Gli3 expression. Muscle tissue of Gli3 +/- mice appeared normal, and Gli3 +/- mice displayed no significant cardiovascular functional anomalies. Capillary density and left-ventricular ejection fractions were reduced in Gli3 +/- mice after surgical induction of myocardial infarction, indicating that Gli3 contributed to ischemic tissue repair. Gli3 +/- mice displayed reduced capillary density after induction of hind-limb ischemia, showing that Gli3 also contributed to vascular growth in ischemic hind limbs. Moreover, Gli3 +/- mice exhibited impaired angiogenic response to vascular endothelial growth factor (VEGFA; <a href="/entry/192240">192240</a>) in the corneal angiogenesis model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19729595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Sheth, R., Marcon, L., Bastida, M. F., Junco, M., Quintana, L., Dahn, R., Kmita M., Sharpe, J., Ros, M. A. <strong>Hox genes regulate digit patterning by controlling the wavelength of a Turing-type mechanism.</strong> Science 338: 1476-1480, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239739</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23239739[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.1226804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239739">Sheth et al. (2012)</a> used mouse genetics to analyze how digit patterning (an iterative digit/nondigit pattern) is generated and showed that the progressive reduction in Hoxa13 (<a href="/entry/142959">142959</a>) and Hoxd11 (<a href="/entry/142986">142986</a>)-Hoxd13 (<a href="/entry/142989">142989</a>) genes (hereafter referred to as distal Hox genes) from the Gli3-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits. Combined with computer modeling, their results argued for a Turing-type mechanism underlying digit patterning, in which the dose of distal Hox genes modulates the digit period or wavelength. The phenotypic similarity of fish-fin endoskeleton patterns suggested that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>'Extra toes' mutant mice (Gli3(Xt-J/Xt-J)) have an intragenic deletion of the Gli3 gene that results in a null allele and have been proposed as a model for GCPS. <a href="#40" class="mim-tip-reference" title="Rice, D. P. C., Connor, E. C., Veltmaat, J. M., Lana-Elola, E., Veistinen, L., Tanimoto, Y., Bellusci, S., Rice, R. <strong>Gli3(Xt-J/Xt-J) mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation.</strong> Hum. Molec. Genet. 19: 3457-3467, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20570969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20570969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20570969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20570969">Rice et al. (2010)</a> showed that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. Gli3(Xt-J/Xt-J) mice exhibited craniosynostosis of the lambdoid sutures that was accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes were preceded by ectopic expression of the Hedgehog (Hh; see <a href="/entry/600725">600725</a>) receptor Patched1 (<a href="/entry/601309">601309</a>) and reduced expression of the transcription factor Twist1 (<a href="/entry/601622">601622</a>) in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2 (<a href="/entry/600211">600211</a>). Runx2 expression in the lambdoid suture was altered in a pattern complementary to that of Twist1. The authors proposed that loss of Gli3 resulted in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation, which results in a bony bridge forming between the parietal and interparietal bones. <a href="#40" class="mim-tip-reference" title="Rice, D. P. C., Connor, E. C., Veltmaat, J. M., Lana-Elola, E., Veistinen, L., Tanimoto, Y., Bellusci, S., Rice, R. <strong>Gli3(Xt-J/Xt-J) mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation.</strong> Hum. Molec. Genet. 19: 3457-3467, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20570969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20570969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20570969[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20570969">Rice et al. (2010)</a> found that FGF2 induced Twist1, normalized osteoprogenitor proliferation and differentiation, and rescued the lambdoid suture synostosis in Gli3(Xt-J/Xt-J) mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20570969" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Western blot and in situ hybridization analyses, <a href="#46" class="mim-tip-reference" title="Tanimoto, Y., Veistinen, L., Alakurtti, K., Takatalo, M., Rice, D. P. <strong>Prevention of premature fusion of calvarial suture in GLI-Kruppel family member 3 (Gli3)-deficient mice by removing one allele of Runt-related transcription factor 2 (Runx2).</strong> J. Biol. Chem. 287: 21429-21438, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22547067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22547067</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22547067[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.362145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22547067">Tanimoto et al. (2012)</a> showed that processing of full-length Gli3 into Gli3r took place in calvarial tissue of wildtype mice, and that Hh signaling occurred in osteogenic front of calvarial sutures. Gli3-deficient mice, which develop craniosynostosis during embryogenesis due to aberrant enhancement of Runx2 (<a href="/entry/600211">600211</a>) expression and reduced Twist1 (<a href="/entry/601622">601622</a>) expression in mid-sutural mesenchymal cells, had aberrantly expressed Dlx5 (<a href="/entry/600028">600028</a>) and Runx2 isoform II in lambdoid sutures. Gli3-deficient Runx2 +/- compound mutant mice did not display craniosynostosis and had no additional ectopic ossification in interfrontal suture. Furthermore, the increased proliferation in interfrontal and lambdoid sutures and the ectopic and upregulated expression of osteoblast differentiation-related genes seen in Gli3-deficient mice were normalized in Gli3-deficient Runx2 +/- mice. The results demonstrated that Gli3 signaling is important to keep Runx2 in check, and that Runx2 dosage is important in maintaining the correct balance of osteogenesis in developing suture. Western blot and immunohistochemical analyses of calvarial tissue from wildtype mice suggested that Gli3 has an important role in cranial suture development through the canonical BMP (see <a href="/entry/112264">112264</a>)-SMAD (see <a href="/entry/601595">601595</a>) pathway involving a Dlx5 (<a href="/entry/600028">600028</a>)-Runx2 isoform II cascade. Consequently, lack of Gli3r led to activation of Bmp signaling through the canonical Smad pathway in mid-sutural mesenchyme, resulting in bone formation and causing craniosynostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22547067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in situ hybridization, <a href="#4" class="mim-tip-reference" title="Bastida, M. F., Perez-Gomez, R., Trofka, A., Zhu, J., Rada-Iglesias, A., Sheth, R., Stadler, H. S., Mackem, S., Ros, M. A. <strong>The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13.</strong> Proc. Nat. Acad. Sci. 117: 1090-1096, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31896583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31896583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31896583[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.1919470117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31896583">Bastida et al. (2020)</a> observed increased Gli3r activity in anterior mesoderm of Hoxa13 -/- mouse embryos, which displayed a limb phenotype with absence of thumb and syndactyly and underwent lethality. Gli3 had a highly dynamic expression pattern in wildtype mice, but in the absence of Hoxa13, the dynamics of Gli3 expression were dramatically altered. Hoxa13 regulated Gli3 expression in the autopod most likely at the transcriptional level by negatively modulating the activity of its enhancers, thereby regulating formation of thumb in wildtype mice. The authors found no evidence of physical interaction between Hoxa13 and Gli3 proteins, supporting the model of transcriptional modulation of Gli3 by Hoxa13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31896583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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GLI3, DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014824" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014824" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014824</a>
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<p>The report of <a href="#34" class="mim-tip-reference" title="Pettigrew, A. L., Greenberg, F., Caskey, C. T., Ledbetter, D. H. <strong>Greig syndrome associated with an interstitial deletion of 7p: confirmation of the localization of Greig syndrome to 7p13.</strong> Hum. Genet. 87: 452-456, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1879832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1879832</a>] [<a href="https://doi.org/10.1007/BF00197167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1879832">Pettigrew et al. (1991)</a> is typical of reports of Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>) in association with large deletions or translocations resulting in haploinsufficiency of the GLI3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1879832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0002 PALLISTER-HALL SYNDROME</strong>
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GLI3, 1-BP DEL, 2023G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840744 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840744;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=rs116840744" 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=rs116840744" 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=RCV000014825" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014825" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014825</a>
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<p>In the exons spanning nucleotides 1813-2103 of the GLI3 cDNA, <a href="#24" class="mim-tip-reference" title="Kang, S., Graham, J. M., Jr., Olney, A. H., Biesecker, L. G. <strong>GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.</strong> Nature Genet. 15: 266-268, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054938</a>] [<a href="https://doi.org/10.1038/ng0397-266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054938">Kang et al. (1997)</a> found by SSCP analysis a different abnormal band in affected members of each of 2 families with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>). In 1 family, the de novo mutation originating the disorder was identified. One family showed a 1-bp deletion (2023G) that predicted a frameshift and premature stop 16 codons 3-prime of the mutation. In a second family they found that 3 affected members were heterozygous for a single-base deletion involving 2012G (<a href="#0003">165240.0003</a>). This deletion resulted in a frameshift and predicted protein termination codon in the same location as that in the other family. The mutations predicted a protein truncated after 691 amino acids, compared to the predicted length of 1,596 amino acids for the normal gene product. These mutant alleles terminate just C-terminal of the zinc finger domains, with 16-20 residues of abnormal protein sequence between the frameshift and the stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9054938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span class="mim-font">
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<strong>.0003 PALLISTER-HALL SYNDROME</strong>
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GLI3, 1-BP DEL, 2012G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840743 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840743;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=rs116840743" 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=rs116840743" 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=RCV000014826" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014826" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014826</a>
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<p>For discussion of the 1-bp deletion in the GLI3 gene (2012G) that was found in compound heterozygous state in patients with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>) by <a href="#24" class="mim-tip-reference" title="Kang, S., Graham, J. M., Jr., Olney, A. H., Biesecker, L. G. <strong>GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.</strong> Nature Genet. 15: 266-268, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054938</a>] [<a href="https://doi.org/10.1038/ng0397-266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054938">Kang et al. (1997)</a>, see <a href="#0002">165240.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9054938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0004" class="mim-anchor"></a>
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<h4>
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<strong>.0004 POSTAXIAL POLYDACTYLY, TYPE A1</strong>
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GLI3, CODON 764, FS
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014827</a>
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<p><a href="#38" class="mim-tip-reference" title="Radhakrishna, U., Wild, A., Grzeschik, K.-H., Antonarakis, S. E. <strong>GLI3 mutations in postaxial polydactyly type A. (Abstract)</strong> Am. J. Hum. Genet. 61 (suppl.): A48 only, 1997."None>Radhakrishna et al. (1997)</a> identified a frameshift mutation at codon 764 in 1 allele of the GLI3 cDNA in all members of an Indian kindred with postaxial polydactyly type A1 (PAPA1; <a href="/entry/174200">174200</a>).</p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 PREAXIAL POLYDACTYLY, TYPE IV</strong>
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</h4>
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GLI3, 1-BP INS, 3647C
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1583729562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583729562;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=rs1583729562" 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=rs1583729562" 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=RCV000014828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014828</a>
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<p>In a large 4-generation family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV (PPD4; <a href="/entry/174700">174700</a>), <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> identified heterozygosity for a 1-bp insertion (c.3647insC) in exon 15 of the GLI3 gene, causing a frameshift predicted to result in a premature termination codon (Leu1216ProfsTer30). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 PALLISTER-HALL SYNDROME</strong>
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GLI3, GLU1147TER
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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> rs116840768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840768;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/rs116840768?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=rs116840768" 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=rs116840768" 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=RCV000014829" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014829" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014829</a>
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<p>In a patient with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>), <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> identified heterozygosity for a 3439G-T transversion in exon 14 of the GLI3 gene, resulting in a nonsense mutation, E1147X. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0007" class="mim-anchor"></a>
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<strong>.0007 POSTAXIAL POLYDACTYLY, TYPE A1/B</strong>
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GLI3, 1-BP DEL, 3707G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1583729398 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583729398;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=rs1583729398" 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=rs1583729398" 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=RCV000014830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014830</a>
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<p><a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> found 3 families with postaxial polydactyly type A/B, i.e., with type A1 and type B (see <a href="/entry/174200">174200</a>) in the same family, and in some cases in the same individual. Linkage analysis showed no recombination with GLI3-linked polymorphisms. One of the families had deletion of G at nucleotide 3707 producing a frameshift and resulting in a truncated protein of 1,280 amino acids after addition of 45 novel codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 POSTAXIAL POLYDACTYLY, TYPE A1/B</strong>
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GLI3, ARG643TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917709;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=rs121917709" 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=rs121917709" 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=RCV000014831 OR RCV001836708 OR RCV004528110" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014831, RCV001836708, RCV004528110" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014831...</a>
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<p>In a family with postaxial polydactyly of mixed type, i.e., with type A1 and type B (see <a href="/entry/174200">174200</a>) in the same family, and in some cases in the same individual, <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> found a 1927C-T transition in the GLI3 gene, resulting in a stop codon (R643X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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GLI3, GLY727ARG
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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> rs121917710 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917710;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/rs121917710?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=rs121917710" 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=rs121917710" 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=RCV000014832 OR RCV000174664 OR RCV000267521 OR RCV000320330 OR RCV000358789 OR RCV000514884 OR RCV001084662 OR RCV003458333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014832, RCV000174664, RCV000267521, RCV000320330, RCV000358789, RCV000514884, RCV001084662, RCV003458333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014832...</a>
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<p>This variant, formerly titled POSTAXIAL POLYDACTYLY, TYPE A1/B, has been reclassified based on a review of the ExAC database by <a href="#18" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 4/19/2018."None>Hamosh (2018)</a>.</p><p>In a family with the A/B form of postaxial polydactyly (see <a href="/entry/174200">174200</a>) in which some members manifested both forms, <a href="#37" class="mim-tip-reference" title="Radhakrishna, U., Bornholdt, D., Scott, H. S., Patel, U. C., Rossier, C., Engel, H., Bottani, A., Chandal, D., Blouin, J.-L., Solanki, J. V., Grzeschik, K.-H., Antonarakis, S. E. <strong>The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; no phenotype prediction from the position of GLI3 mutations.</strong> Am. J. Hum. Genet. 65: 645-655, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441570</a>] [<a href="https://doi.org/10.1086/302557" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441570">Radhakrishna et al. (1999)</a> found a missense mutation, gly727 to arg, in a highly conserved amino acid at domain 3 of the GLI3 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 4/19/2018."None>Hamosh (2018)</a> found that the G727R variant was present in heterozygous state in 693 of 121,412 alleles and in 4 homozygotes, with an allele frequency of 0.005, in the ExAC database (April 19, 2018).</p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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GLI3, GLU543TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917711 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917711;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=rs121917711" 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=rs121917711" 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=RCV000014833" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014833" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014833</a>
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<p>In 24 patients with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#23" class="mim-tip-reference" title="Kalff-Suske, M., Wild, A., Topp, J., Wessling, M., Jacobsen, E.-M., Bornholdt, D., Engel, H., Heuer, H., Aalfs, C. M., Ausems, M. G. E. M., Barone, R., Herzog, A., and 11 others. <strong>Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.</strong> Hum. Molec. Genet. 8: 1769-1777, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441342</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441342">Kalff-Suske et al. (1999)</a> identified 15 novel mutations, one of which was a G-to-T transversion at nucleotide 1627 of the GLI3 gene, resulting in a glu543-to-ter mutation. Five generations of their family J were said to have been affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#45" class="mim-tip-reference" title="Sobetzko, D., Eich, G., Kalff-Suske, M., Grzeschik, K.-H., Superti-Furga, A. <strong>Boy with syndactylies, macrocephaly, and severe skeletal dysplasia: not a new syndrome, but two dominant mutations (GLI3 E543X and COL2A1 G973R) in the same individual.</strong> Am. J. Med. Genet. 90: 239-242, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10678662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10678662</a>]" pmid="10678662">Sobetzko et al. (2000)</a> identified this mutation in conjunction with a gly973-to-arg mutation in the COL2A1 gene (G973R; <a href="/entry/120140#0031">120140.0031</a>) in a boy with an unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia. The patient combined the Greig syndrome with a severe form of spondyloepiphyseal dysplasia congenita (SEDC; <a href="/entry/183900">183900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10678662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 PALLISTER-HALL SYNDROME</strong>
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GLI3, 72-BP INS mtDNA, EX14
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014834" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014834" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014834</a>
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<p>In a sporadic case of Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>), previously described by <a href="#33" class="mim-tip-reference" title="Ozerov, S. S., Khukhlaeva, E. A., Pronin, I. N., Trubanova, N. G. <strong>The Pallister-Hall syndrome--a rare case and an example of the differentiated approach to the treatment of hormonally inactive hypothalamic hamartomas.</strong> Zh. Vopr. Neirokhir. Im. N. N. Burdenko Jan.-Mar.: 40-42, 1997. Note: Article in Russian.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9148633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9148633</a>]" pmid="9148633">Ozerov et al. (1997)</a>, <a href="#50" class="mim-tip-reference" title="Turner, C., Killoran, C., Thomas, N. S. T., Rosenberg, M., Chuzhanova, N. A., Johnston, J., Kemel, Y., Cooper, D. N., Biesecker, L. G. <strong>Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer.</strong> Hum. Genet. 112: 303-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545275</a>] [<a href="https://doi.org/10.1007/s00439-002-0892-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545275">Turner et al. (2003)</a> identified a 72-bp insertion of mtDNA into exon 14 of the GLI3 gene, creating a premature stop codon predicting a truncated protein product. The patient had a hypothalamic hamartoma demonstrated by cranial MRI without endocrine abnormalities or seizures. He had scars on his hands consistent with removal of a supernumerary ulnar digit, fusion of his metacarpals, and a bifid epiglottis. <a href="#50" class="mim-tip-reference" title="Turner, C., Killoran, C., Thomas, N. S. T., Rosenberg, M., Chuzhanova, N. A., Johnston, J., Kemel, Y., Cooper, D. N., Biesecker, L. G. <strong>Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer.</strong> Hum. Genet. 112: 303-309, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545275</a>] [<a href="https://doi.org/10.1007/s00439-002-0892-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545275">Turner et al. (2003)</a> found heterozygosity for the insertion, which was not found in the parents. The authors performed analysis of a SNP, which indicated that the allele with the 72-bp insertion had a C at position 2993 of the GLI3 cDNA (wildtype, T), and that the mother was a T/T homozygote and the father a C/T heterozygote. Thus the mutated allele was of paternal origin. The insertion was found to be identical to a region partially overlapping 2 mitochondrial tRNA genes, MTTS2 (<a href="/entry/590085">590085</a>) and MTTL2 (<a href="/entry/590055">590055</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12545275+9148633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 GREIG CEPHALOPOLYSYNDACTYLY 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">rs121917712 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917712;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=rs121917712" 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=rs121917712" 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=RCV000014835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014835</a>
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<p>In a 4-generation family in which 9 members with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>) were studied clinically and molecularly, <a href="#11" class="mim-tip-reference" title="Debeer, P., Peeters, H., Driess, S., De Smet, L., Freese, K., Matthijs, G., Bornholdt, D., Devriendt, K., Grzeschik, K.-H., Fryns, J.-P., Kalff-Suske, M. <strong>Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations.</strong> Am. J. Med. Genet. 120A: 49-58, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794692</a>] [<a href="https://doi.org/10.1002/ajmg.a.20018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794692">Debeer et al. (2003)</a> found an arg625-to-trp (R625W) missense mutation in the GLI3 gene that was partially penetrant. In one branch of the family, the GCPS phenotype skipped a generation via a normal female carrier without clinical signs, providing evidence that GCPS does not always manifest full penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0013 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME, SEVERE</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">rs28933372 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933372;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=rs28933372" 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=rs28933372" 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=RCV000030896" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030896" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030896</a>
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<p>In a child with agenesis of the corpus callosum and severe retardation, both cardinal features of acrocallosal syndrome (ACLS; <a href="/entry/200990">200990</a>) and rare in Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#14" class="mim-tip-reference" title="Elson, E., Perveen, R., Donnai, D., Wall, S., Black, G. C. M. <strong>De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models.</strong> J. Med. Genet. 39: 804-806, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12414818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12414818</a>] [<a href="https://doi.org/10.1136/jmg.39.11.804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12414818">Elson et al. (2002)</a> identified a heterozygous 2800G-C transversion in exon 15 of the GLI3 gene, resulting in an ala934-to-pro (A934P) mutation. At birth, he had bilateral cleft lip and palate, a large anterior fontanel extending down his forehead, overriding coronal sutures, and small ears with uplifted lobes. Pronounced hypertelorism was present and cranial MRI showed agenesis of the corpus callosum. His hands showed bilateral postaxial nubbins, a broad thumb on the right hand, and a partially duplicated left thumb. There was also partial cutaneous syndactyly bilaterally. The feet displayed bilateral duplication of the big toe and syndactyly of the other toes. At the chronologic age of 56 months he was estimated to have a mental age of 21 months. We have classified the phenotype in this patient as GCPS based on the identification of a heterozygous mutation in GLI3 as opposed to homozygous mutations in KIF7 (<a href="/entry/611254">611254</a>), which have been identified in patients with ACLS. <a href="#7" class="mim-tip-reference" title="Biesecker, L. G. <strong>The Grieg polysyndactyly syndrome.</strong> Orphanet J. Rare Dis. 3: 10, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18435847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18435847</a>] [<a href="https://doi.org/10.1186/1750-1172-3-10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18435847">Biesecker (2008)</a> stated that patients with a phenotype consistent with GCPS and a GLI3 mutation may be diagnosed definitively as GCPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18435847+12414818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0014 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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PREAXIAL POLYDACTYLY, TYPE IV, INCLUDED
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GLI3, ARG290TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917713 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917713;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=rs121917713" 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=rs121917713" 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=RCV000014837 OR RCV000014838 OR RCV000554724" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014837, RCV000014838, RCV000554724" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014837...</a>
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<p>In 4 unrelated families with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#21" class="mim-tip-reference" title="Johnston, J. J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J. T., Peters, K. F., Abbott, M. H., Aughton, D. J., Aylsworth, A. S., Bamshad, M. J., Booth, C., Curry, C. J., and 36 others. <strong>Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.</strong> Am. J. Hum. Genet. 76: 609-622, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15739154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15739154</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15739154[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15739154">Johnston et al. (2005)</a> identified an 868C-T transition in exon 7 of the GLI3 gene, resulting in an arg290-to-ter (R290X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15739154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with preaxial polydactyly type IV (<a href="/entry/174700">174700</a>), <a href="#15" class="mim-tip-reference" title="Fujioka, H., Ariga, T., Horiuchi, K., Otsu, M., Igawa, H., Kawashima, K., Yamamoto, Y., Sugihara, T., Sakiyama, Y. <strong>Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I.</strong> Clin. Genet. 67: 429-433, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811011</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00431.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811011">Fujioka et al. (2005)</a> identified heterozygosity for an R290X mutation in the GLI3 gene. The patient had duplications of both proximal and distal phalanges of both feet, syndactyly of the first and second toes on the right and of the second and third toes on the left, and syndactyly of the third and fourth fingers on his left hand but no other syndromic anomalies. His father, who was also heterozygous for the mutation, had bilateral foot preaxial polydactyly with syndactyly of the first and second toes, but no hand abnormalities. The unaffected mother did not have the mutation. <a href="#5" class="mim-tip-reference" title="Biesecker, L. G., Johnston, J. <strong>Syndromic and non-syndromic GLI3 phenotypes. (Letter)</strong> Clin. Genet. 68: 284 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098019</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.0485a.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098019">Biesecker and Johnston (2005)</a> raised the question of whether there was sufficient phenotypic evidence to rule out a diagnosis of GCPS in the father and son reported by <a href="#15" class="mim-tip-reference" title="Fujioka, H., Ariga, T., Horiuchi, K., Otsu, M., Igawa, H., Kawashima, K., Yamamoto, Y., Sugihara, T., Sakiyama, Y. <strong>Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I.</strong> Clin. Genet. 67: 429-433, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15811011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15811011</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00431.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15811011">Fujioka et al. (2005)</a>. <a href="#16" class="mim-tip-reference" title="Fujioka, H., Ariga, T. <strong>Response to Biesecker and Johnston. (Letter)</strong> Clin. Genet. 68: 285 only, 2005."None>Fujioka and Ariga (2005)</a> noted that <a href="#2" class="mim-tip-reference" title="Baraitser, M., Winter, R. M., Brett, E. M. <strong>Greig cephalopolysyndactyly: report of 13 affected individuals in three families.</strong> Clin. Genet. 24: 257-265, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6641002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6641002</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1983.tb00080.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6641002">Baraitser et al. (1983)</a> had reported that facial features of Greig syndrome can be so mild as to be indistinguishable from normal and had suggested that preaxial polydactyly type IV may be Greig syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15811011+16098019+6641002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 POSTAXIAL POLYDACTYLY, TYPE B</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">rs1583734240 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583734240;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=rs1583734240" 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=rs1583734240" 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=RCV000014839" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014839" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014839</a>
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<p>In a patient with postaxial polydactyly type B (PAPB; see <a href="/entry/174200">174200</a>) affecting both hands, <a href="#17" class="mim-tip-reference" title="Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. <strong>Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.</strong> Am. J. Med. Genet. 143A: 3150-3160, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000979</a>] [<a href="https://doi.org/10.1002/ajmg.a.32097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000979">Furniss et al. (2007)</a> identified a heterozygous 1-bp deletion (2372delC) in exon 14 of the GLI3 gene, predicted to cause a frameshift and premature termination. Further studies indicated that the mutation resulted in nonsense-mediated mRNA decay. The patient's father had unilateral PAPB and an obligate carrier in the family was unaffected, indicating variable expressivity and reduced penetrance. <a href="#17" class="mim-tip-reference" title="Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. <strong>Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.</strong> Am. J. Med. Genet. 143A: 3150-3160, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000979</a>] [<a href="https://doi.org/10.1002/ajmg.a.32097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000979">Furniss et al. (2007)</a> postulated that the relatively mild phenotype may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0016 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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GLI3, ARG792TER
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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> rs121917714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917714;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/rs121917714?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=rs121917714" 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=rs121917714" 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=RCV000014840 OR RCV000489344 OR RCV001047666 OR RCV001450016 OR RCV004732544 OR RCV005031437" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014840, RCV000489344, RCV001047666, RCV001450016, RCV004732544, RCV005031437" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014840...</a>
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<p>In a patient with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#17" class="mim-tip-reference" title="Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. <strong>Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.</strong> Am. J. Med. Genet. 143A: 3150-3160, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000979</a>] [<a href="https://doi.org/10.1002/ajmg.a.32097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000979">Furniss et al. (2007)</a> identified a heterozygous 2374C-T transition in exon 14 of the GLI3 gene, resulting in an arg792-to-ter (R792X) substitution. The mutation was demonstrated to result in nonsense-mediated mRNA decay. <a href="#17" class="mim-tip-reference" title="Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. <strong>Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3.</strong> Am. J. Med. Genet. 143A: 3150-3160, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000979</a>] [<a href="https://doi.org/10.1002/ajmg.a.32097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000979">Furniss et al. (2007)</a> postulated that the relatively mild phenotype in this patient, which was less severe than that observed in Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>), may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0017 PALLISTER-HALL SYNDROME</strong>
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</h4>
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GLI3, 19-BP DEL, NT2188
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs116840754 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116840754;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=rs116840754" 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=rs116840754" 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=RCV000014841" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014841" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014841</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with Pallister-Hall syndrome (PHS; <a href="/entry/146510">146510</a>), <a href="#26" class="mim-tip-reference" title="Killoran, C. E., Abbott, M., McKusick, V. A., Biesecker, L. G. <strong>Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.</strong> Clin. Genet. 58: 28-30, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945658</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.580105.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945658">Killoran et al. (2000)</a> identified heterozygosity for a 19-bp deletion of nucleotides 2188-2207 in exon 14 of the GLI3 gene resulting in a frameshift and predicting a truncated protein of 731 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0018" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0018 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</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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<div style="float: left;">
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GLI3, GLN496TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121917715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917715;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=rs121917715" 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=rs121917715" 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=RCV000014842" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014842" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014842</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a mother and daughter with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#57" class="mim-tip-reference" title="Wild, A., Kalff-Suske, M., Vortkamp, A., Bornholdt, D., Konig, R., Grzeschik, K.-H. <strong>Point mutations in human GLI3 cause Greig syndrome.</strong> Hum. Molec. Genet. 6: 1979-1984, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302279</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302279">Wild et al. (1997)</a> identified a heterozygous 1485C-T transition in exon 10 of the GLI3 gene, resulting in a gln496-to-ter (Q496X) substitution in the first zinc finger-binding domain, predicted to eliminate the DNA-binding potential of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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<div>
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<a id="0019" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0019 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</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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<div style="float: left;">
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GLI3, PRO707SER
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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> rs121917716 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121917716;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/rs121917716?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=rs121917716" 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=rs121917716" 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=RCV000014843 OR RCV000500441 OR RCV000508658 OR RCV000542657 OR RCV000782254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014843, RCV000500441, RCV000508658, RCV000542657, RCV000782254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014843...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#57" class="mim-tip-reference" title="Wild, A., Kalff-Suske, M., Vortkamp, A., Bornholdt, D., Konig, R., Grzeschik, K.-H. <strong>Point mutations in human GLI3 cause Greig syndrome.</strong> Hum. Molec. Genet. 6: 1979-1984, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302279</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302279">Wild et al. (1997)</a> identified a heterozygous 2119C-T transition in exon 14 of the GLI3 gene, resulting in a pro707-to-ser (P707S) substitution. The mutation occurred in a conserved residue in a putative phosphorylation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0020" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0020 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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</span>
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</h4>
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</div>
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GLI3, 4-BP DEL, 4542CCAC
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2128704804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2128704804;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=rs2128704804" 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=rs2128704804" 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=RCV000014844" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014844" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014844</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient with a variant of Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#30" class="mim-tip-reference" title="McDonald-McGinn, D. M., Feret, H., Nah, H.-D., Bartlett, S. P., Whitaker, L. A., Zackai, E. H. <strong>Metopic craniosynostosis due to mutations in GLI3: a novel association.</strong> Am. J. Med. Genet. 152A: 1654-1660, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20583172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20583172</a>] [<a href="https://doi.org/10.1002/ajmg.a.33495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20583172">McDonald-McGinn et al. (2010)</a> identified a heterozygous 4-bp deletion (4542delCCAC) in exon 14 of the GLI3 gene, resulting in a frameshift and premature termination. Parental studies were normal. The patient had metopic craniosynostosis resulting in trigonocephaly, upslanting palpebral fissures, and full-digit postaxial polydactyly of all 4 limbs. There were no structural brain anomalies and development was normal at age 14 months. The presence of trigonocephaly expanded the phenotype associated with GLI3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20583172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="0021" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0021 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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</span>
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</h4>
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GLI3, 1-BP DEL, 1018A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1583500982 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583500982;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=rs1583500982" 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=rs1583500982" 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=RCV000014845" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014845" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014845</a>
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<p>In a boy with a variant of Greig cephalopolysyndactyly syndrome (GCPS; <a href="/entry/175700">175700</a>), <a href="#30" class="mim-tip-reference" title="McDonald-McGinn, D. M., Feret, H., Nah, H.-D., Bartlett, S. P., Whitaker, L. A., Zackai, E. H. <strong>Metopic craniosynostosis due to mutations in GLI3: a novel association.</strong> Am. J. Med. Genet. 152A: 1654-1660, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20583172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20583172</a>] [<a href="https://doi.org/10.1002/ajmg.a.33495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20583172">McDonald-McGinn et al. (2010)</a> identified a heterozygous 1-bp deletion (1018delA) in exon 6 of the GLI3 gene, resulting in a frameshift and premature termination. Parental studies were normal. The patient had metopic craniosynostosis resulting in trigonocephaly, relative hypertelorism, and multiple digital anomalies, including bilateral complete cutaneous syndactyly of the third and fourth fingers, duplication of the great toe on the right with soft tissue syndactyly of toes 2 and 3, and medial deviation of the great toe on the left. There were no structural brain anomalies and development was normal at age 13 years. The presence of trigonocephaly expanded the phenotype associated with GLI3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20583172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 POSTAXIAL POLYDACTYLY, TYPE A1/B</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">rs398122899 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122899;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=rs398122899" 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=rs398122899" 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=RCV000032707" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032707" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032707</a>
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<p>In affected members of a 3-generation nonconsanguineous Saudi Arabian family with postaxial polydactyly (<a href="/entry/174200">174200</a>), <a href="#1" class="mim-tip-reference" title="Al-Qattan, M. M. <strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong> Clin. Genet. 82: 502-504, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22428873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22428873</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01866.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22428873">Al-Qattan (2012)</a> identified heterozygosity for a 2-bp deletion (1615delGA) in the GLI3 gene, predicted to cause a frameshift resulting in a premature termination codon (R539Tfs*12). <a href="#1" class="mim-tip-reference" title="Al-Qattan, M. M. <strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong> Clin. Genet. 82: 502-504, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22428873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22428873</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01866.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22428873">Al-Qattan (2012)</a> noted that although this frameshift predicts truncation in the N-terminal part of the gene and a GCPS phenotype would be expected, none of the family members had craniofacial features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22428873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Al-Qattan, M. M.
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<strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong>
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Clin. Genet. 82: 502-504, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22428873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22428873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22428873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2012.01866.x" target="_blank">Full Text</a>]
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Baraitser, M., Winter, R. M., Brett, E. M.
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<strong>Greig cephalopolysyndactyly: report of 13 affected individuals in three families.</strong>
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Clin. Genet. 24: 257-265, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6641002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6641002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6641002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1983.tb00080.x" target="_blank">Full Text</a>]
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Barna, M., Pandolfi, P. P., Niswander, L.
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<strong>Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. (Letter)</strong>
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Nature 436: 277-281, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16015334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16015334</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16015334" 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/nature03801" target="_blank">Full Text</a>]
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Bastida, M. F., Perez-Gomez, R., Trofka, A., Zhu, J., Rada-Iglesias, A., Sheth, R., Stadler, H. S., Mackem, S., Ros, M. A.
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<strong>The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13.</strong>
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Proc. Nat. Acad. Sci. 117: 1090-1096, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31896583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31896583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31896583[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=31896583" 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/10.1073/pnas.1919470117" target="_blank">Full Text</a>]
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Biesecker, L. G., Johnston, J.
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<strong>Syndromic and non-syndromic GLI3 phenotypes. (Letter)</strong>
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Clin. Genet. 68: 284 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098019</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16098019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2005.0485a.x" target="_blank">Full Text</a>]
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Biesecker, L. G.
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<strong>What you can learn from one gene: GLI3.</strong>
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J. Med. Genet. 43: 465-469, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16740916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16740916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16740916[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=16740916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.029181" target="_blank">Full Text</a>]
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Biesecker, L. G.
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<strong>The Grieg polysyndactyly syndrome.</strong>
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Orphanet J. Rare Dis. 3: 10, 2008. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18435847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18435847</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18435847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bose, J., Grotewold, L., Ruther, U.
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<strong>Pallister-Hall syndrome phenotype in mice mutant for Gli3.</strong>
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Hum. Molec. Genet. 11: 1129-1135, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978771</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978771" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Brueton, L., Huson, S. M., Winter, R. M., Williamson, R.
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<strong>Chromosomal localisation of a developmental gene in man: direct DNA analysis demonstrates that Greig cephalopolysyndactyly maps to 7p13.</strong>
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Am. J. Med. Genet. 31: 799-804, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3239571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3239571</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3239571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320310412" target="_blank">Full Text</a>]
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Craig, D. W., Itty, A., Panganiban, C., Szelinger, S., Kruer, M. C., Sekar, A., Reiman, D., Narayanan, V., Stephan, D. A., Kerrigan, J. F.
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<strong>Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus.</strong>
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Am. J. Hum. Genet. 82: 366-374, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252217</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252217[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=18252217" 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.2007.10.006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20018" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2014.62" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.62426" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.39.11.804" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.M112.362145" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.2002.6798" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0892-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1429" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.94.26.14900" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80678-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0509927103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/6.11.1979" target="_blank">Full Text</a>]
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Woischnik, M., Moraes, C. T.
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<strong>Pattern of organization of human mitochondrial pseudogenes in the nuclear genome.</strong>
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Genome Res. 12: 885-893, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12045142[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=12045142" 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/10.1101/gr.227202" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/01/2024
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<span class="mim-text-font">
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Bao Lige - updated : 12/12/2022<br>Bao Lige - updated : 12/01/2022<br>Ada Hamosh - updated : 04/19/2018<br>Ada Hamosh - updated : 04/16/2018<br>Patricia A. Hartz - updated : 2/26/2016<br>Ingrid M. Wentzensen - updated : 4/21/2015<br>George E. Tiller - updated : 9/26/2013<br>Marla J. F. O'Neill - updated : 2/11/2013<br>Ada Hamosh - updated : 1/14/2013<br>Ada Hamosh - updated : 5/24/2012<br>Cassandra L. Kniffin - updated : 10/27/2010<br>Patricia A. Hartz - updated : 10/5/2009<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Carol A. Bocchini - updated : 2/10/2009<br>Cassandra L. Kniffin - updated : 1/12/2009<br>Victor A. McKusick - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 10/12/2006<br>Victor A. McKusick - updated : 7/5/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Ada Hamosh - updated : 8/18/2005<br>Marla J. F. O'Neill - updated : 6/24/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Victor A. McKusick - updated : 1/10/2005<br>Victor A. McKusick - updated : 5/4/2004<br>Victor A. McKusick - updated : 6/23/2003<br>Victor A. McKusick - updated : 3/25/2003<br>George E. Tiller - updated : 12/17/2002<br>Ada Hamosh - updated : 11/19/2002<br>Ada Hamosh - updated : 9/13/2002<br>Stylianos E. Antonarakis - updated : 4/5/2000<br>Victor A. McKusick - updated : 2/25/2000<br>Victor A. McKusick - updated : 10/28/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Victor A. McKusick - updated : 4/20/1999<br>Ada Hamosh - updated : 4/9/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 10/24/1997<br>Victor A. McKusick - updated : 3/2/1997
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Victor A. McKusick : 10/6/1988
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carol : 02/02/2024
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carol : 02/01/2024<br>mgross : 12/12/2022<br>mgross : 12/01/2022<br>alopez : 05/02/2019<br>carol : 05/03/2018<br>carol : 04/17/2018<br>alopez : 04/16/2018<br>carol : 08/23/2016<br>mgross : 02/26/2016<br>mgross : 2/26/2016<br>alopez : 10/2/2015<br>carol : 7/22/2015<br>carol : 5/21/2015<br>mcolton : 4/21/2015<br>carol : 12/10/2014<br>carol : 6/19/2014<br>carol : 6/18/2014<br>ckniffin : 6/18/2014<br>alopez : 9/26/2013<br>carol : 9/16/2013<br>carol : 9/6/2013<br>carol : 2/11/2013<br>alopez : 1/16/2013<br>terry : 1/14/2013<br>carol : 5/24/2012<br>terry : 5/24/2012<br>alopez : 8/4/2011<br>wwang : 11/11/2010<br>ckniffin : 10/27/2010<br>mgross : 10/5/2009<br>terry : 10/5/2009<br>wwang : 8/5/2009<br>ckniffin : 7/21/2009<br>carol : 2/10/2009<br>carol : 2/10/2009<br>ckniffin : 1/12/2009<br>terry : 10/8/2008<br>alopez : 5/1/2008<br>alopez : 4/3/2008<br>terry : 3/31/2008<br>wwang : 10/18/2006<br>ckniffin : 10/12/2006<br>alopez : 7/7/2006<br>terry : 7/5/2006<br>wwang : 3/20/2006<br>terry : 3/13/2006<br>carol : 12/21/2005<br>carol : 8/26/2005<br>alopez : 8/23/2005<br>alopez : 8/23/2005<br>terry : 8/18/2005<br>wwang : 7/20/2005<br>wwang : 7/18/2005<br>terry : 6/24/2005<br>wwang : 3/14/2005<br>terry : 3/11/2005<br>alopez : 2/10/2005<br>wwang : 1/25/2005<br>terry : 1/10/2005<br>tkritzer : 5/21/2004<br>terry : 5/4/2004<br>terry : 7/31/2003<br>cwells : 6/27/2003<br>terry : 6/23/2003<br>tkritzer : 4/8/2003<br>tkritzer : 4/2/2003<br>terry : 3/25/2003<br>cwells : 12/17/2002<br>alopez : 11/19/2002<br>terry : 11/15/2002<br>alopez : 9/13/2002<br>mgross : 4/5/2000<br>alopez : 2/25/2000<br>mgross : 10/28/1999<br>alopez : 10/27/1999<br>alopez : 10/26/1999<br>alopez : 10/26/1999<br>terry : 9/24/1999<br>mgross : 4/27/1999<br>mgross : 4/21/1999<br>terry : 4/20/1999<br>carol : 12/4/1998<br>alopez : 4/9/1998<br>mark : 12/9/1997<br>terry : 12/2/1997<br>terry : 10/28/1997<br>mark : 10/25/1997<br>terry : 10/24/1997<br>terry : 8/21/1997<br>jamie : 3/4/1997<br>mark : 3/2/1997<br>terry : 2/27/1997<br>terry : 9/12/1994<br>carol : 5/16/1994<br>carol : 6/22/1993<br>supermim : 3/16/1992<br>carol : 3/8/1992<br>carol : 10/2/1991
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<span class="mim-font">
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<strong>*</strong> 165240
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<h3>
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<span class="mim-font">
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GLI-KRUPPEL FAMILY MEMBER 3; GLI3
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ONCOGENE GLI3
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GLI3</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 32985001, 56677004, 715707008;
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<strong>
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<em>
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Cytogenetic location: 7p14.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:41,960,949-42,264,268 </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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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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7p14.1
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Greig cephalopolysyndactyly syndrome
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<span class="mim-font">
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175700
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Autosomal dominant
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3
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Pallister-Hall syndrome
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<span class="mim-font">
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146510
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Autosomal dominant
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<span class="mim-font">
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3
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Polydactyly, postaxial, types A1 and B
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<span class="mim-font">
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174200
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<span class="mim-font">
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Autosomal dominant
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3
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Polydactyly, preaxial, type IV
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<span class="mim-font">
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174700
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>GLI3 encodes a zinc finger transcription factor that functions in the hedgehog (Hh; see SHH, 600725) signal transduction pathway, which is dependent on primary cilia in many tissues. GLI3 undergoes posttranslational maturation into 2 isoforms with antagonistic transcriptional activities. SHH signaling causes proteolytic processing of GLI3 into a peptide, GLI3A, with transcriptional activator function. In the absence of SHH signaling, GLI3 is processed to a shorter peptide, GLI3R, with transcriptional repressor function. Processing of GLI3 to either form requires the primary cilium (summary by Laclef et al., 2015). </p>
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<strong>Cloning and Expression</strong>
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<p>Like GLI2 (165230), the GLI3 gene was isolated by virtue of its cross-hybridization to the zinc finger gene GLI (165220), which is amplified in certain glioblastomas and represents a potential sequence-specific DNA-binding transcription factor from the GLI-Kruppel gene family. The GLI3 gene is expressed as an 8.5-kb mRNA in tissues such as testis, myometrium, placenta, and lung, and the protein product (relative molecular mass, 190,000) shows sequence-specific DNA binding (Ruppert et al., 1988; Ruppert et al., 1990). The gene encodes a predicted 1,596-amino acid polypeptide. </p>
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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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<p>Vortkamp et al. (1994) isolated a YAC contig of more than 1,000 kb, including the GLI3 gene. In this contig the gene itself spanned at least 200 to 250 kb. A CpG island was located in the vicinity of the 5-prime region of the GLI3 cDNA, implying a potential promoter region. Kang et al. (1997) demonstrated that the coding region of GLI3 is composed of 14 exons, including a large exon of more than 2,500 bp. In addition, the gene contains 2 intragenic dinucleotide repeats, and 4 single-basepair polymorphisms in the coding region. Kang et al. (1997) used these coding region polymorphisms to design an allele-specific expression study useful for investigating patients with Greig syndrome (GCPS; 175700). </p><p>Wild et al. (1997) stated that the GLI3 gene contains 15 exons spanning 240 kb. The zinc finger domain is contained within 4 exons (10 through 13). Exon 1 is untranslated. </p><p>Osterwalder et al. (2018) showed that the pervasive presence of multiple enhancers with similar activities near the same gene confers phenotypic robustness to loss-of-function mutations in individual enhancers. Osterwalder et al. (2018) used genome editing to create 23 mouse deletion lines and intercrosses, including both single and combinatorial enhancer deletions at 7 distinct loci required for limb development including Gli3, Shox2 (602504), Tbx3 (601621), Tbx5 (601620), and Lhx5 (605992). Unexpectedly, none of the 10 deletions of individual enhancers caused noticeable changes in limb morphology. By contrast, the removal of pairs of limb enhancers near the same gene resulted in discernible phenotypes, indicating that enhancers function redundantly in establishing normal morphology. In a genetic background sensitized by reduced baseline expression of the target gene, even single enhancer deletions caused limb abnormalities, suggesting that functional redundancy is conferred by additive effects of enhancers on gene expression levels. A genomewide analysis integrating epigenomic and transcriptomic data from 29 developmental mouse tissues revealed that mammalian genes are very commonly associated with multiple enhancers that have similar spatiotemporal activity. Systematic exploration of 3 representative developmental structures (limb, brain, and heart) uncovered more than 1,000 cases in which 5 or more enhancers with redundant activity patterns were found near the same gene. Osterwalder et al. (2018) concluded that their data indicated that enhancer redundancy is a remarkably widespread feature of mammalian genomes that provides an effective regulatory buffer to prevent deleterious phenotypic consequences upon the loss of individual enhancers. </p>
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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>Ruppert et al. (1988) mapped the GLI3 gene to chromosome 7 by analysis of DNA from human-rodent hybrid panels. Using in situ hybridization, Ruppert et al. (1990) mapped the GLI3 gene to chromosome 7p13. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</div>
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<span class="mim-text-font">
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<p>Although GLI1, located on 12q13, has been associated with glioma, GLI3 has not been related to glioma or other form of neoplasia (Vogelstein, 1994).</p><p>For a review of the role of the GLI3 gene in limb development, see Johnson and Tabin (1997). </p><p>GLI3 is homologous to the Drosophila cubitus interruptus (ci) gene product (Ci), which regulates the Patched (pct), gooseberry (gsb), and decapentaplegic (dpp) genes. Ci is sequestered in the cytoplasm and is subject to posttranslational processing whereby the full-length transcriptional activator form with 155 amino acids (Ci-155) can be cleaved to a repressor form with 75 amino acids (Ci-75). Under hedgehog (see 600725) signaling, Ci-155 translocates to the nucleus, whereas in the absence of hedgehog, Ci-75 translocates to the nucleus. Based on the correlation of GLI3 truncation mutations and the human phenotypes, Shin et al. (1999) hypothesized that GLI3 shows transcriptional activation or repression activity and subcellular localization similar to Ci. They showed that full-length GLI3 localizes to the cytoplasm and activates PTCH (601309) gene expression, which is similar to full-length Ci-155. </p><p>Wang et al. (2000) demonstrated that PKA (see 176911)-dependent processing of vertebrate GLI3 in developing limb generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized SHH. They concluded that the resulting anterior/posterior GLI3 repressor gradient can be perturbed by mutations of the GLI3 gene in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid-2, producing a range of limb patterning malformations. The high relative abundance and potency of GLI3 repressor suggested specialization of GLI3 and its products for negative hedgehog pathway regulation. </p><p>Wang and Li (2006) demonstrated that overexpression of BTRC (603482), the vertebrate homolog of Drosophila Slimb, resulted in an increase in GLI3 repressor, whereas RNA interference of BTRC blocked GLI3 processing. BTRC could bind directly to phosphorylated GLI3 in vitro and in vivo, suggesting that it acts downstream of PKA, GSK3 (see 605004), and CK1 (600505) in the processing pathway. Coimmunoprecipitation and immunoblot studies showed that GLI3 protein is polyubiquitinated and that its processing depends on proteasome activity. The findings suggested that BTRC is required for GLI3 processing. </p><p>Using knockdown and overexpression analyses, Renault et al. (2009) showed that GLI3 regulated function and gene expression in human umbilical vein endothelial cells (HUVECs). GLI3 activated the AKT (164730) pathway and the MAPK-ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) pathway in HUVECs, and GLI3-induced endothelial cell migration was dependent on both AKT and MAPK-ERK1/ERK2 activation. However, luciferase reporter assays revealed that GLI3 overexpression did not modulate GLI-dependent transcription. </p><p>Laclef et al. (2015) found that deletion of the ciliopathy gene Rpgrip1l (610937) in mice caused abnormal corticoseptal boundary formation in medial telencephalon, leading to disturbed location of guidepost cells in dorsomedial telencephalon and agenesis of corpus callosum. Deletion of the ciliary transcription factor Rfx3 (601337) results in a similar, but less severe, phenotype in mouse embryos. In both cases, overexpression of a Gli3 mutant with premature termination at codon 699, resulting in production of only a short Gli3 protein functionally similar to Gli3r, rescued corpus callosum formation, guidepost organization, and midline patterning. However, expression of the Gli3 mutant did not rescue ventral telencephalic phenotypes in Rfx3 -/- or Rpgrip1l -/- mutants. Laclef et al. (2015) concluded that cilia are required for telencephalon patterning and that GLI3 has a major role in development of the corpus callosum. </p><p>Mastocytosis is a hematologic malignancy characterized by clonal accumulation of mast cells in 1 or more organs. A somatic mutation in KIT (164920), asp816 to val (D816V; 164920.0009), is present in about 85% of patients with mastocytosis. Using RT-PCR, immunofluorescence, and Western blot analyses, Polivka et al. (2021) showed that the Hh pathway was activated in neoplastic mast cells (MCs) from patients with mastocytosis and GCPS, and that the Hh signaling pathway cooperated with constitutively activate KIT in the onset of mastocytosis. Analysis with a GCPS mouse model revealed that mutated Gli3 synergized with the Kit D816V mutant to promote tumorigenicity, as Gli3 haploinsufficiency and high Gli3a/Gli3r ratio inhibited apoptosis and enhanced proliferation, especially when Kit was mutated. Analysis with HMC1.2 cells confirmed that Gli3 was a tumor suppressor, as expression of GLI3R drastically inhibited proliferation of HMC1.2 cells. Analysis with Hh antagonists confirmed that the Hh pathway was essential for MC transformation, and inhibition of the Hh pathway suppressed neoplastic MC proliferation in vitro and extended the survival time of mice with aggressive systemic mastocytosis. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Greig Cephalopolysyndactyly Syndrome</em></strong></p><p>
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Pettigrew et al. (1991) identified large deletions in the GLI3 gene in patients with Greig cephalopolysyndactyly syndrome (GCPS; 175700) (see, e.g., 165240.0001). Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been found in association with GCPS (Pettigrew et al., 1991; Vortkamp et al., 1991; Brueton et al., 1988), although no mutations were identified in GCPS patients with normal karyotypes. </p><p>In patients with GCPS, Wild et al. (1997) identified heterozygous point mutations in the GLI3 gene (165240.0018 and 165240.0019). </p><p>Kalff-Suske et al. (1999) performed GLI3 mutation analysis on 24 GCPS patients. They identified 15 novel mutations (see, e.g., 165240.0010) present in heterozygous state in the patients' GLI3 alleles. The mutations mapped throughout the coding gene regions. Most were truncating mutations (9 of 15) that engendered prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. The 5 mutations identified within the protein regions C-terminal to the zinc fingers putatively affected additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to 2 adjacent independent domains in the C-terminal third of GLI3. Since these were the only functional domains affected by 3 C-terminally truncating mutations, Kalff-Suske et al. (1999) postulated that GCPS may be due either to the haploinsufficiency resulting from complete loss of 1 gene copy, or to functional haploinsufficiency related to compromised properties of this transcription factor, such as DNA binding and transactivation. </p><p>Biesecker (2008) reviewed GCPS, noting the phenotypic overlap with acrocallosal syndrome (ACLS; 200990). He remarked that in patients with substantial phenotypic overlap, molecular diagnostics are essential to arrive at a correct diagnosis; a mutation in GLI3 denotes GCPS. </p><p><strong><em>Pallister-Hall Syndrome</em></strong></p><p>
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Kang et al. (1997) identified frameshift mutations in the GLI3 gene (e.g., 165240.0002) in patients with Pallister-Hall syndrome (PHS; 146510). </p><p>Numerous fragments of mitochondrial DNA migrated from the mitochondrial genome to the nuclear genome over evolutionary time (Wallace et al., 1997; Mourier et al., 2001; Tourmen et al., 2002; Woischnik and Moraes, 2002). Mitochondrial DNA insertion polymorphisms can be used for human population studies (Thomas et al., 1996). This process of mitochondria-to-nucleus DNA migration has the consequence that the extant mitochondrial proteome is now overwhelmingly encoded by the nuclear genome. Turner et al. (2003) described a sporadic case of Pallister-Hall syndrome in which a de novo mitochondrial-nuclear translocation resulted in functional disruption of the GLI3 gene (165240.0011). </p><p><strong><em>Postaxial Polydactyly</em></strong></p><p>
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Postaxial polydactyly type A1 (PAPA1; 174200) is an autosomal trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is usually functional, since it is well formed and articulates with the fifth or extrametacarpal/metatarsal. The gene responsible for this trait was mapped to the centromeric region of 7p by Radhakrishna et al. (1997). Since the GLI3 gene maps to the same region, Radhakrishna et al. (1997) performed a mutation search in GLI3 cDNA from an Indian family with PAPA1 and demonstrated a mutation at codon 764 in 1 GLI3 allele. The mutation occurred 3-prime to the conserved domain termed Pzf1 (post zinc finger-1). Haploinsufficiency GLI3 is associated with some cases of GCPS, whereas frameshift mutations 3-prime to the zinc finger domains but upstream of the Pzf1 domain cause the Pallister-Hall syndrome. Thus, the coding of presumably different truncated GLI3 proteins are associated with different clinical syndromes, suggesting specific roles for the variant protein domains during development. </p><p>In a patient with postaxial polydactyly type B (PAPB; see 174200) affecting both hands, Furniss et al. (2007) identified a heterozygous 1-bp deletion (2372delC; 165240.0015) in the GLI3 gene. </p><p>In affected members of a 3-generation nonconsanguineous Saudi Arabian family with postaxial polydactyly, Al-Qattan (2012) identified heterozygosity for a 2-bp deletion (1615delGA; 165240.0022) in the GLI3 gene. Al-Qattan (2012) noted that although this frameshift predicts truncation in the N-terminal part of the gene and a GCPS phenotype would be expected, none of the family members had craniofacial features. </p><p><strong><em>Preaxial Polydactyly Type IV</em></strong></p><p>
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In a large 4-generation family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV (PPD4; 174700), Radhakrishna et al. (1999) identified heterozygosity for a 1-bp insertion in the GLI3 gene (165240.0005) that segregated with disease. </p><p>In a father and son with PPD4, Fujioka et al. (2005) identified heterozygosity for a nonsense mutation in the GLI3 gene (R290X; 165240.0014). </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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Approximately 5% of cases of hypothalamic hamartomas (HH; see 241800) are associated with Pallister-Hall syndrome (PHS; 146510), which is caused by haploinsufficiency of GLI3. Craig et al. (2008) investigated the possibility that HH pathogenesis in sporadic cases is due to a somatic (tumor-only) mutation in GLI3. They isolated genomic DNA from peripheral blood and surgically resected HH tissue in 55 patients with sporadic HH and intractable epilepsy. A genomewide screen for loss of heterozygosity (LOH) and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue with Affymetrix 10K SNP microarrays. Additionally, resequencing and fine mapping with SNP genotyping were completed for the GLI3 gene with comparisons between peripheral blood and HH tissue pairs. By analyzing chromosomal copy number data for paired samples on the array, Craig et al. (2008) identified a somatic chromosomal abnormality on chromosome 7p in one HH tissue sample. Resequencing of GLI3 did not identify causative germline mutations but did identify LOH within the GLI3 gene in the HH tissue samples of 3 patients. Further genotyping of 28 SNPs within and surrounding GLI3 identified 5 additional patients exhibiting LOH. Together, these data provided evidence that the development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, nonsyndromic patients with HH and intractable epilepsy. Chromosomal abnormalities including the GLI3 locus were seen in 8 of 55 (15%) of the resected HH tissue samples. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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El Mouatani et al. (2021) reported 3 unrelated patients with polydactyly, some with other features, and homozygous variants in the GLI3 gene. The first patient was a 10-year-old girl, born of first-cousin parents from Afghanistan, with bilateral postaxial polydactyly of the hands and dysmorphic facial features including flat face, hypertelorism, short philtrum, pointed chin, and microcephaly (-2 SD). She had global developmental delay and marked speech delay. She had craniosynostosis, conductive hearing loss, hyperopia and astigmatism, velar and submucosal cleft palate, bifid uvula, gingival growths, short tongue frenulum, oligodontia with short dysplastic teeth, and complete agenesis of the corpus callosum. A targeted 148 gene panel identified a homozygous missense variant in exon 5 (c.668G-A, NM_000168.5; S223N). Both parents were heterozygous for the variant and had no evidence of polydactyly. No functional evidence was provided. The variant was present in 4 of 251,214 alleles in only heterozygous state in the gnomAD database. The second patient was a 2-month-old male, born to first cousins of North African ancestry. Both parents had an unremarkable medical history, but on the mother's side there were relatives with polydactyly and on the father's side there were relatives with syndactyly and a neurodevelopmental disorder. The patient was born with bilateral polysyndactyly of hands and feet and a deviated, proximally placed thumb. He also had an epigastric and umbilical hernia. Brain MRI was unremarkable. Sanger sequencing of GLI3 exons and flanking intronic sequences identified a homozygous missense variant in exon 12 (c.1673C-T, NM_000168.5, S558L). Both parents were carriers. The variant was not present in the gnomAD database. No functional testing was performed, and no other genes were sequenced. The third patient was a 42-year-old man with bilateral mesoaxial polydactyly of the hands. He had a flat face, short philtrum, and a height of 1.61 m (-2 SD), severely impaired intellectual development, limited language, sensorineural hearing loss, strabismus, bilateral ptosis, ophthalmoplegia, short and large uvula, and short penis. Brain MRI showed hypoplastic corpus callosum, vermian atrophy (molar tooth sign), and retrocerebellar cyst. A targeted 96 gene panel showed homozygosity for a missense variant (c.565_567delinsTCT, NM_000168.5; P189S). His mother carried the variant, but his father was not available for testing. In the gnomAD database, the variant was present as 2 rare phased variants (rs201940674 and rs371984494) in only heterozygous state. No functional testing was performed. Hamosh (2024) noted that in gnomAD on 1/31/24, the S223N variant was present 16 times; the S558L variant was present once; and the P189S variant was present 300 times for a highest population frequency of 0.00108 in the Ashkenazi Jewish population. She also noted that the P189S variant was labeled as likely benign by 2 groups in ClinVar (1/31/24). </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Shin et al. (1999) found that the mutant GLI3 protein of the Pallister-Hall syndrome localizes to the nucleus and represses GLI3-activated PTCH expression, which is similar to Ci-75. The mutant protein of Greig cephalopolysyndactyly syndrome has no effect on GLI3-activated PTCH transcription, consistent with the role of haploinsufficiency in this disorder. The mutant GLI3 protein of type A1 postaxial polysyndactyly showed less specific subcellular localization but still inhibited GLI3-activated PTCH transcription, suggesting that it may be a weaker allele than the Pallister-Hall mutation. These data showed that GLI3 mutations in humans mimic the functional effects of the Drosophila ci gene and correlate with the distinct effects of these mutations on human development. </p><p>Kalff-Suske et al. (1999) provided a summary of known GLI3 mutations in GCPS, PHS, and PAPA1. </p><p>Up to 1999, mutations in the GLI3 gene had been identified in Greig cephalopolysyndactyly, Pallister-Hall syndrome, and postaxial polydactyly type A. Radhakrishna et al. (1999) demonstrated a 1-nucleotide frameshift insertion (165240.0005) resulting in a truncated protein of 1,245 amino acids in a family with preaxial polydactyly type IV (174700). They found a frameshift mutation due to a 1-nucleotide deletion (165240.0007) in affected members of a family with dominant postaxial polydactyly type A/B (with type A and type B in the same family). In 2 other families with a mixed form of postaxial polydactyly, a nonsense mutation (R643X; 165240.0008) was found in one and a missense mutation (G727R; 165240.0009) in the other. A patient with Pallister-Hall syndrome had a nonsense mutation (E1147X; 165240.0006). These results added 2 phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. Phenotype could not be predicted from the position of the GLI3 mutations. Radhakrishna et al. (1999) proposed that all phenotypes associated with GLI3 mutations be called 'GLI3 morphopathies,' since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation. </p><p>Johnston et al. (2005) hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause Pallister-Hall syndrome, whereas haploinsufficiency of GLI3 causes Greig cephalopolysyndactyly syndrome. To test this hypothesis, they screened 46 patients with PHS and 89 patients with GCPS for GLI3 mutations. They detected 47 pathologic mutations (among 60 probands), and when these mutations were combined with previously published mutations, 2 genotype-phenotype correlations were evident. GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Among the frameshift/nonsense mutations, Johnston et al. (2005) found a clear genotype/phenotype correlation. Mutations in the first third of the gene (from open reading frame nucleotides 1-1997) caused GCPS, and mutations in the second third of the gene (from nucleotides 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3-prime third of the gene (after open reading frame nucleotide 3481), and no patients with PHS had mutations in this region. These results demonstrated a robust genotype/phenotype correlation for GLI3 mutations and strongly supported the hypothesis that these 2 allelic disorders have distinct modes of pathogenesis. </p><p>Biesecker (2006) reviewed 'what you can learn from one gene: GLI3.' He pointed out that the mutations in GLI3 that cause Pallister-Hall syndrome and those that cause Greig cephalopolysyndactyly correlate with the phenotypes on 2 levels: many types of inactivating mutations cause GCPS, whereas PHS is caused almost exclusively by truncation mutations in the middle third of the gene. This mutational correlation is supported by in vitro and animal model experimentation showing that the truncation mutations correlate with the posttranslational regulation of the gene, which is accomplished by proteolytic processing to give GLI3 both a transcriptional repressor and activator effect. Thus, GLI3 is a bifunctional transcriptional switch and these attributes correlate with the phenotype. The PHS and GCPS phenotypes caused by GLI3 mutations are qualitatively distinct but both encompass a wide range of severity that may include nonsyndromic polydactyly. </p><p>Johnston et al. (2010) reported results from a cohort of 93 probands referred for GLI3 analysis: mutations were identified in 11 (65%) of 17 probands fulfilling criteria for GCPS, in 1 (50%) of 2 probands with PHS, in 8 (29%) of 28 probands with features overlapping GCPS, in 8 (40%) of 20 probands with features overlapping PHS, in 6 (29%) of 21 patients with features of orofaciodigital syndrome (OFD; see 311200) in addition to 1 or more features of GCPS or PHS, and in 1 (20%) of 5 probands with isolated PAPA. Johnston et al. (2010) noted that the combination of these data with those of their previous work (Johnston et al., 2005) showed that patients manifesting features sufficient for clinical diagnosis of PHS or GCPS have a high chance of having a mutation in GLI3 (91% and 68%, respectively). The finding of GLI3 mutations in patients with features of OFD supported the observation that GLI3 interacts with cilia. Johnston et al. (2010) concluded that the phenotypic spectrum of GLI3 mutations was broader than that encompassed by the clinical diagnostic criteria, but that the genotype/phenotype correlation persisted. </p><p>Demurger et al. (2015) reported the molecular and clinical results from their study of a cohort of 76 probands with either a GLI3 mutation (49 with GCPS and 21 with PHS) or a large deletion encompassing the GLI3 gene (6 with GCPS). Most (41) of the reported mutations were novel and supported previously reported genotype/phenotype correlations. Truncating mutations in the middle third of the gene generally resulted in PHS, whereas exonic deletions and missense and truncating mutations elsewhere in the gene caused GCPS. </p>
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<strong>Animal Model</strong>
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<p>Litingtung et al. (2002) reported genetic analyses in mice showing that Shh and Gli3 are dispensable for formation of limb skeletal elements. The limbs of double-knockout Shh/Gli mice are distally complete and polydactylous, but completely lack wildtype digit identities. Litingtung et al. (2002) showed that the effects of Shh signaling on skeletal patterning and ridge maintenance are necessarily mediated through Gli3. The authors proposed that the function of Shh and Gli3 in limb skeletal patterning is limited to refining autopodial morphology, imposing pentadactyl constraint on the limb's polydactyl potential, and organizing digit identity specification, by regulating the relative balance of Gli3 transcriptional activator and repressor activities. </p><p>Te Welscher et al. (2002) reported that the polydactyly of Gli3-deficient mice arises independently of Shh signaling. Disruption of one or both Gli3 alleles in mouse embryos lacking Shh progressively restored limb distal development and digit formation. Te Welscher et al. (2002) concluded that SHH signaling counteracts GLI3-mediated repression of key regulator genes, cell survival, and distal progression of limb bud development. The limbs of Gli3-deficient embryos were polydactylous, whereas 1 fused forearm bone and no digit arch formed in limbs of Shh-deficient embryos. Disruption of 1 Gli3 allele on an Shh-knockout background resulted in embryos with 2 forearm bones and rudimentary digits. The limbs of double homozygous mouse embryos were grossly morphologically indistinguishable from the limbs of Gli3 homozygous embryos. Te Welscher et al. (2002) showed that, whereas the polydactyly of Gli3 -/- mice is Shh-independent, the polydactyly of Alx4 (605420) mutant mice depends on Shh signaling. </p><p>Bose et al. (2002) produced transgenic mice homozygous for a mutation lying 3-prime to the zinc finger DNA-binding domain of Gli3. These mice, which died shortly after birth, exhibited central polydactyly as well as a wide range of developmental abnormalities encompassing almost all of the common PHS features, including imperforate anus; gastrointestinal, epiglottis, and larynx defects; abnormal kidney development; and absence of adrenal glands. TUNEL assays revealed a decrease in apoptosis within the interdigital webs of these animals, although MSX2 (123101) expression, which is also involved in this process, was apparently not affected. </p><p>Barna et al. (2005) identified a genetic interaction between Gli3 and Plzf (176797) that is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot were relatively unperturbed in Gli3/Plzf double knockout mouse embryos. Barna et al. (2005) demonstrated that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb bud independently of proximal-distal (P-D) patterning markers and overall limb bud size. Moreover, the limb defects in the double knockout embryos correlated with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor type 1B (Bmpr1b; 603248) at the onset of limb development. Barna et al. (2005) concluded that development of proximal and distal skeletal elements is distinctly regulated during early limb bud formation. The initial division of the vertebrate limb into 2 distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins. </p><p>Matera et al. (2008) found that homozygosity for a null mutation of Gli3 (tyr350 to ter) in mice was embryonic lethal. Heterozygous mutant mice exhibited numerous skeletal defects, and a portion of them exhibited ventral hypopigmentation. Homozygous mutant embryos had a reduced number of early-stage melanoblasts. Neural crest cells from homozygous mutant embryos differentiated into highly pigmented melanocytes in culture, and skin from homozygous mutant mice produced pigment in skin grafts, suggesting that Gli3-deficient melanoblasts are able to terminally differentiate. Heterozygosity for the Gli3 mutation increased the penetrance and severity of the hypopigmentation phenotype of Sox10 (602229) +/- mice, a model for human Waardenburg syndrome (277580). A C-terminal truncation mutant of Gli3 that retained its transcriptional repressor function, but not the activator domain, was sufficient to induce melanoblast differentiation in mouse embryos. Matera et al. (2008) concluded that the repressor function of GLI3 is required for melanoblast specification. </p><p>Using RT-PCR analysis, Renault et al. (2009) confirmed that Gli3 +/- mice were haploinsufficient with significantly reduced Gli3 expression. Muscle tissue of Gli3 +/- mice appeared normal, and Gli3 +/- mice displayed no significant cardiovascular functional anomalies. Capillary density and left-ventricular ejection fractions were reduced in Gli3 +/- mice after surgical induction of myocardial infarction, indicating that Gli3 contributed to ischemic tissue repair. Gli3 +/- mice displayed reduced capillary density after induction of hind-limb ischemia, showing that Gli3 also contributed to vascular growth in ischemic hind limbs. Moreover, Gli3 +/- mice exhibited impaired angiogenic response to vascular endothelial growth factor (VEGFA; 192240) in the corneal angiogenesis model. </p><p>Sheth et al. (2012) used mouse genetics to analyze how digit patterning (an iterative digit/nondigit pattern) is generated and showed that the progressive reduction in Hoxa13 (142959) and Hoxd11 (142986)-Hoxd13 (142989) genes (hereafter referred to as distal Hox genes) from the Gli3-null background results in progressively more severe polydactyly, displaying thinner and densely packed digits. Combined with computer modeling, their results argued for a Turing-type mechanism underlying digit patterning, in which the dose of distal Hox genes modulates the digit period or wavelength. The phenotypic similarity of fish-fin endoskeleton patterns suggested that the pentadactyl state has been achieved through modification of an ancestral Turing-type mechanism. </p><p>'Extra toes' mutant mice (Gli3(Xt-J/Xt-J)) have an intragenic deletion of the Gli3 gene that results in a null allele and have been proposed as a model for GCPS. Rice et al. (2010) showed that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. Gli3(Xt-J/Xt-J) mice exhibited craniosynostosis of the lambdoid sutures that was accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes were preceded by ectopic expression of the Hedgehog (Hh; see 600725) receptor Patched1 (601309) and reduced expression of the transcription factor Twist1 (601622) in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2 (600211). Runx2 expression in the lambdoid suture was altered in a pattern complementary to that of Twist1. The authors proposed that loss of Gli3 resulted in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation, which results in a bony bridge forming between the parietal and interparietal bones. Rice et al. (2010) found that FGF2 induced Twist1, normalized osteoprogenitor proliferation and differentiation, and rescued the lambdoid suture synostosis in Gli3(Xt-J/Xt-J) mice. </p><p>By Western blot and in situ hybridization analyses, Tanimoto et al. (2012) showed that processing of full-length Gli3 into Gli3r took place in calvarial tissue of wildtype mice, and that Hh signaling occurred in osteogenic front of calvarial sutures. Gli3-deficient mice, which develop craniosynostosis during embryogenesis due to aberrant enhancement of Runx2 (600211) expression and reduced Twist1 (601622) expression in mid-sutural mesenchymal cells, had aberrantly expressed Dlx5 (600028) and Runx2 isoform II in lambdoid sutures. Gli3-deficient Runx2 +/- compound mutant mice did not display craniosynostosis and had no additional ectopic ossification in interfrontal suture. Furthermore, the increased proliferation in interfrontal and lambdoid sutures and the ectopic and upregulated expression of osteoblast differentiation-related genes seen in Gli3-deficient mice were normalized in Gli3-deficient Runx2 +/- mice. The results demonstrated that Gli3 signaling is important to keep Runx2 in check, and that Runx2 dosage is important in maintaining the correct balance of osteogenesis in developing suture. Western blot and immunohistochemical analyses of calvarial tissue from wildtype mice suggested that Gli3 has an important role in cranial suture development through the canonical BMP (see 112264)-SMAD (see 601595) pathway involving a Dlx5 (600028)-Runx2 isoform II cascade. Consequently, lack of Gli3r led to activation of Bmp signaling through the canonical Smad pathway in mid-sutural mesenchyme, resulting in bone formation and causing craniosynostosis. </p><p>By in situ hybridization, Bastida et al. (2020) observed increased Gli3r activity in anterior mesoderm of Hoxa13 -/- mouse embryos, which displayed a limb phenotype with absence of thumb and syndactyly and underwent lethality. Gli3 had a highly dynamic expression pattern in wildtype mice, but in the absence of Hoxa13, the dynamics of Gli3 expression were dramatically altered. Hoxa13 regulated Gli3 expression in the autopod most likely at the transcriptional level by negatively modulating the activity of its enhancers, thereby regulating formation of thumb in wildtype mice. The authors found no evidence of physical interaction between Hoxa13 and Gli3 proteins, supporting the model of transcriptional modulation of Gli3 by Hoxa13. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>22 Selected Examples):</strong>
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<strong>.0001 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
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GLI3, DEL
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ClinVar: RCV000014824
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<p>The report of Pettigrew et al. (1991) is typical of reports of Greig cephalopolysyndactyly syndrome (GCPS; 175700) in association with large deletions or translocations resulting in haploinsufficiency of the GLI3 gene. </p>
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<strong>.0002 PALLISTER-HALL SYNDROME</strong>
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GLI3, 1-BP DEL, 2023G
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SNP: rs116840744,
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ClinVar: RCV000014825
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<p>In the exons spanning nucleotides 1813-2103 of the GLI3 cDNA, Kang et al. (1997) found by SSCP analysis a different abnormal band in affected members of each of 2 families with Pallister-Hall syndrome (PHS; 146510). In 1 family, the de novo mutation originating the disorder was identified. One family showed a 1-bp deletion (2023G) that predicted a frameshift and premature stop 16 codons 3-prime of the mutation. In a second family they found that 3 affected members were heterozygous for a single-base deletion involving 2012G (165240.0003). This deletion resulted in a frameshift and predicted protein termination codon in the same location as that in the other family. The mutations predicted a protein truncated after 691 amino acids, compared to the predicted length of 1,596 amino acids for the normal gene product. These mutant alleles terminate just C-terminal of the zinc finger domains, with 16-20 residues of abnormal protein sequence between the frameshift and the stop codon. </p>
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<strong>.0003 PALLISTER-HALL SYNDROME</strong>
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<div>
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<span class="mim-text-font">
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GLI3, 1-BP DEL, 2012G
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<br />
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SNP: rs116840743,
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|
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ClinVar: RCV000014826
|
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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 1-bp deletion in the GLI3 gene (2012G) that was found in compound heterozygous state in patients with Pallister-Hall syndrome (PHS; 146510) by Kang et al. (1997), see 165240.0002. </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">
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<strong>.0004 POSTAXIAL POLYDACTYLY, TYPE A1</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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GLI3, CODON 764, FS
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<br />
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ClinVar: RCV000014827
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|
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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>Radhakrishna et al. (1997) identified a frameshift mutation at codon 764 in 1 allele of the GLI3 cDNA in all members of an Indian kindred with postaxial polydactyly type A1 (PAPA1; 174200).</p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 PREAXIAL POLYDACTYLY, TYPE IV</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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GLI3, 1-BP INS, 3647C
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<br />
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|
SNP: rs1583729562,
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|
|
ClinVar: RCV000014828
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|
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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 large 4-generation family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV (PPD4; 174700), Radhakrishna et al. (1999) identified heterozygosity for a 1-bp insertion (c.3647insC) in exon 15 of the GLI3 gene, causing a frameshift predicted to result in a premature termination codon (Leu1216ProfsTer30). </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PALLISTER-HALL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
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|
GLI3, GLU1147TER
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<br />
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SNP: rs116840768,
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|
|
gnomAD: rs116840768,
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|
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ClinVar: RCV000014829
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Pallister-Hall syndrome (PHS; 146510), Radhakrishna et al. (1999) identified heterozygosity for a 3439G-T transversion in exon 14 of the GLI3 gene, resulting in a nonsense mutation, E1147X. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 POSTAXIAL POLYDACTYLY, TYPE A1/B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
GLI3, 1-BP DEL, 3707G
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|
<br />
|
|
|
|
SNP: rs1583729398,
|
|
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|
|
|
|
|
ClinVar: RCV000014830
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Radhakrishna et al. (1999) found 3 families with postaxial polydactyly type A/B, i.e., with type A1 and type B (see 174200) in the same family, and in some cases in the same individual. Linkage analysis showed no recombination with GLI3-linked polymorphisms. One of the families had deletion of G at nucleotide 3707 producing a frameshift and resulting in a truncated protein of 1,280 amino acids after addition of 45 novel codons. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 POSTAXIAL POLYDACTYLY, TYPE A1/B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
GLI3, ARG643TER
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<br />
|
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|
|
SNP: rs121917709,
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|
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|
|
ClinVar: RCV000014831, RCV001836708, RCV004528110
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with postaxial polydactyly of mixed type, i.e., with type A1 and type B (see 174200) in the same family, and in some cases in the same individual, Radhakrishna et al. (1999) found a 1927C-T transition in the GLI3 gene, resulting in a stop codon (R643X). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, GLY727ARG
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|
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|
|
|
<br />
|
|
|
|
SNP: rs121917710,
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|
|
|
|
|
gnomAD: rs121917710,
|
|
|
|
|
|
ClinVar: RCV000014832, RCV000174664, RCV000267521, RCV000320330, RCV000358789, RCV000514884, RCV001084662, RCV003458333
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled POSTAXIAL POLYDACTYLY, TYPE A1/B, has been reclassified based on a review of the ExAC database by Hamosh (2018).</p><p>In a family with the A/B form of postaxial polydactyly (see 174200) in which some members manifested both forms, Radhakrishna et al. (1999) found a missense mutation, gly727 to arg, in a highly conserved amino acid at domain 3 of the GLI3 protein. </p><p>Hamosh (2018) found that the G727R variant was present in heterozygous state in 693 of 121,412 alleles and in 4 homozygotes, with an allele frequency of 0.005, in the ExAC database (April 19, 2018).</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, GLU543TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917711,
|
|
|
|
|
|
|
|
ClinVar: RCV000014833
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 24 patients with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Kalff-Suske et al. (1999) identified 15 novel mutations, one of which was a G-to-T transversion at nucleotide 1627 of the GLI3 gene, resulting in a glu543-to-ter mutation. Five generations of their family J were said to have been affected. </p><p>Sobetzko et al. (2000) identified this mutation in conjunction with a gly973-to-arg mutation in the COL2A1 gene (G973R; 120140.0031) in a boy with an unusual combination of syndactylies, macrocephaly, and severe skeletal dysplasia. The patient combined the Greig syndrome with a severe form of spondyloepiphyseal dysplasia congenita (SEDC; 183900). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PALLISTER-HALL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, 72-BP INS mtDNA, EX14
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000014834
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of Pallister-Hall syndrome (PHS; 146510), previously described by Ozerov et al. (1997), Turner et al. (2003) identified a 72-bp insertion of mtDNA into exon 14 of the GLI3 gene, creating a premature stop codon predicting a truncated protein product. The patient had a hypothalamic hamartoma demonstrated by cranial MRI without endocrine abnormalities or seizures. He had scars on his hands consistent with removal of a supernumerary ulnar digit, fusion of his metacarpals, and a bifid epiglottis. Turner et al. (2003) found heterozygosity for the insertion, which was not found in the parents. The authors performed analysis of a SNP, which indicated that the allele with the 72-bp insertion had a C at position 2993 of the GLI3 cDNA (wildtype, T), and that the mother was a T/T homozygote and the father a C/T heterozygote. Thus the mutated allele was of paternal origin. The insertion was found to be identical to a region partially overlapping 2 mitochondrial tRNA genes, MTTS2 (590085) and MTTL2 (590055). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, ARG625TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917712,
|
|
|
|
|
|
|
|
ClinVar: RCV000014835
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-generation family in which 9 members with Greig cephalopolysyndactyly syndrome (GCPS; 175700) were studied clinically and molecularly, Debeer et al. (2003) found an arg625-to-trp (R625W) missense mutation in the GLI3 gene that was partially penetrant. In one branch of the family, the GCPS phenotype skipped a generation via a normal female carrier without clinical signs, providing evidence that GCPS does not always manifest full penetrance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME, SEVERE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, ALA934PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933372,
|
|
|
|
|
|
|
|
ClinVar: RCV000030896
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with agenesis of the corpus callosum and severe retardation, both cardinal features of acrocallosal syndrome (ACLS; 200990) and rare in Greig cephalopolysyndactyly syndrome (GCPS; 175700), Elson et al. (2002) identified a heterozygous 2800G-C transversion in exon 15 of the GLI3 gene, resulting in an ala934-to-pro (A934P) mutation. At birth, he had bilateral cleft lip and palate, a large anterior fontanel extending down his forehead, overriding coronal sutures, and small ears with uplifted lobes. Pronounced hypertelorism was present and cranial MRI showed agenesis of the corpus callosum. His hands showed bilateral postaxial nubbins, a broad thumb on the right hand, and a partially duplicated left thumb. There was also partial cutaneous syndactyly bilaterally. The feet displayed bilateral duplication of the big toe and syndactyly of the other toes. At the chronologic age of 56 months he was estimated to have a mental age of 21 months. We have classified the phenotype in this patient as GCPS based on the identification of a heterozygous mutation in GLI3 as opposed to homozygous mutations in KIF7 (611254), which have been identified in patients with ACLS. Biesecker (2008) stated that patients with a phenotype consistent with GCPS and a GLI3 mutation may be diagnosed definitively as GCPS. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PREAXIAL POLYDACTYLY, TYPE IV, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, ARG290TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121917713,
|
|
|
|
|
|
|
|
ClinVar: RCV000014837, RCV000014838, RCV000554724
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 unrelated families with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Johnston et al. (2005) identified an 868C-T transition in exon 7 of the GLI3 gene, resulting in an arg290-to-ter (R290X) substitution. </p><p>In a patient with preaxial polydactyly type IV (174700), Fujioka et al. (2005) identified heterozygosity for an R290X mutation in the GLI3 gene. The patient had duplications of both proximal and distal phalanges of both feet, syndactyly of the first and second toes on the right and of the second and third toes on the left, and syndactyly of the third and fourth fingers on his left hand but no other syndromic anomalies. His father, who was also heterozygous for the mutation, had bilateral foot preaxial polydactyly with syndactyly of the first and second toes, but no hand abnormalities. The unaffected mother did not have the mutation. Biesecker and Johnston (2005) raised the question of whether there was sufficient phenotypic evidence to rule out a diagnosis of GCPS in the father and son reported by Fujioka et al. (2005). Fujioka and Ariga (2005) noted that Baraitser et al. (1983) had reported that facial features of Greig syndrome can be so mild as to be indistinguishable from normal and had suggested that preaxial polydactyly type IV may be Greig syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 POSTAXIAL POLYDACTYLY, TYPE B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, 1-BP DEL, 2372C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1583734240,
|
|
|
|
|
|
|
|
ClinVar: RCV000014839
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with postaxial polydactyly type B (PAPB; see 174200) affecting both hands, Furniss et al. (2007) identified a heterozygous 1-bp deletion (2372delC) in exon 14 of the GLI3 gene, predicted to cause a frameshift and premature termination. Further studies indicated that the mutation resulted in nonsense-mediated mRNA decay. The patient's father had unilateral PAPB and an obligate carrier in the family was unaffected, indicating variable expressivity and reduced penetrance. Furniss et al. (2007) postulated that the relatively mild phenotype may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
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|
</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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GLI3, ARG792TER
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<br />
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SNP: rs121917714,
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|
|
|
gnomAD: rs121917714,
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ClinVar: RCV000014840, RCV000489344, RCV001047666, RCV001450016, RCV004732544, RCV005031437
|
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|
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|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Furniss et al. (2007) identified a heterozygous 2374C-T transition in exon 14 of the GLI3 gene, resulting in an arg792-to-ter (R792X) substitution. The mutation was demonstrated to result in nonsense-mediated mRNA decay. Furniss et al. (2007) postulated that the relatively mild phenotype in this patient, which was less severe than that observed in Pallister-Hall syndrome (PHS; 146510), may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein. </p>
|
|
</span>
|
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</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0017 PALLISTER-HALL SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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|
<span class="mim-text-font">
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|
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GLI3, 19-BP DEL, NT2188
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<br />
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SNP: rs116840754,
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ClinVar: RCV000014841
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with Pallister-Hall syndrome (PHS; 146510), Killoran et al. (2000) identified heterozygosity for a 19-bp deletion of nucleotides 2188-2207 in exon 14 of the GLI3 gene resulting in a frameshift and predicting a truncated protein of 731 amino acids. </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>.0018 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
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GLI3, GLN496TER
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<br />
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SNP: rs121917715,
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ClinVar: RCV000014842
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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 mother and daughter with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Wild et al. (1997) identified a heterozygous 1485C-T transition in exon 10 of the GLI3 gene, resulting in a gln496-to-ter (Q496X) substitution in the first zinc finger-binding domain, predicted to eliminate the DNA-binding potential of the protein. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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GLI3, PRO707SER
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<br />
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SNP: rs121917716,
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gnomAD: rs121917716,
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|
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ClinVar: RCV000014843, RCV000500441, RCV000508658, RCV000542657, RCV000782254
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with Greig cephalopolysyndactyly syndrome (GCPS; 175700), Wild et al. (1997) identified a heterozygous 2119C-T transition in exon 14 of the GLI3 gene, resulting in a pro707-to-ser (P707S) substitution. The mutation occurred in a conserved residue in a putative phosphorylation site. </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>.0020 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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GLI3, 4-BP DEL, 4542CCAC
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<br />
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SNP: rs2128704804,
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|
|
ClinVar: RCV000014844
|
|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a variant of Greig cephalopolysyndactyly syndrome (GCPS; 175700), McDonald-McGinn et al. (2010) identified a heterozygous 4-bp deletion (4542delCCAC) in exon 14 of the GLI3 gene, resulting in a frameshift and premature termination. Parental studies were normal. The patient had metopic craniosynostosis resulting in trigonocephaly, upslanting palpebral fissures, and full-digit postaxial polydactyly of all 4 limbs. There were no structural brain anomalies and development was normal at age 14 months. The presence of trigonocephaly expanded the phenotype associated with GLI3 mutations. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 GREIG CEPHALOPOLYSYNDACTYLY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
GLI3, 1-BP DEL, 1018A
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<br />
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|
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SNP: rs1583500982,
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|
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|
|
ClinVar: RCV000014845
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with a variant of Greig cephalopolysyndactyly syndrome (GCPS; 175700), McDonald-McGinn et al. (2010) identified a heterozygous 1-bp deletion (1018delA) in exon 6 of the GLI3 gene, resulting in a frameshift and premature termination. Parental studies were normal. The patient had metopic craniosynostosis resulting in trigonocephaly, relative hypertelorism, and multiple digital anomalies, including bilateral complete cutaneous syndactyly of the third and fourth fingers, duplication of the great toe on the right with soft tissue syndactyly of toes 2 and 3, and medial deviation of the great toe on the left. There were no structural brain anomalies and development was normal at age 13 years. The presence of trigonocephaly expanded the phenotype associated with GLI3 mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 POSTAXIAL POLYDACTYLY, TYPE A1/B</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GLI3, 2-BP DEL, 1615GA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122899,
|
|
|
|
|
|
|
|
ClinVar: RCV000032707
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation nonconsanguineous Saudi Arabian family with postaxial polydactyly (174200), Al-Qattan (2012) identified heterozygosity for a 2-bp deletion (1615delGA) in the GLI3 gene, predicted to cause a frameshift resulting in a premature termination codon (R539Tfs*12). Al-Qattan (2012) noted that although this frameshift predicts truncation in the N-terminal part of the gene and a GCPS phenotype would be expected, none of the family members had craniofacial features. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
|
|
</div>
|
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|
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Al-Qattan, M. M.
|
|
<strong>A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter)</strong>
|
|
Clin. Genet. 82: 502-504, 2012.
|
|
|
|
|
|
[PubMed: 22428873]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2012.01866.x]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Baraitser, M., Winter, R. M., Brett, E. M.
|
|
<strong>Greig cephalopolysyndactyly: report of 13 affected individuals in three families.</strong>
|
|
Clin. Genet. 24: 257-265, 1983.
|
|
|
|
|
|
[PubMed: 6641002]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.1983.tb00080.x]
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|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Barna, M., Pandolfi, P. P., Niswander, L.
|
|
<strong>Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development. (Letter)</strong>
|
|
Nature 436: 277-281, 2005.
|
|
|
|
|
|
[PubMed: 16015334]
|
|
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|
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[Full Text: https://doi.org/10.1038/nature03801]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bastida, M. F., Perez-Gomez, R., Trofka, A., Zhu, J., Rada-Iglesias, A., Sheth, R., Stadler, H. S., Mackem, S., Ros, M. A.
|
|
<strong>The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13.</strong>
|
|
Proc. Nat. Acad. Sci. 117: 1090-1096, 2020.
|
|
|
|
|
|
[PubMed: 31896583]
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|
[Full Text: https://doi.org/10.1073/pnas.1919470117]
|
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|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Biesecker, L. G., Johnston, J.
|
|
<strong>Syndromic and non-syndromic GLI3 phenotypes. (Letter)</strong>
|
|
Clin. Genet. 68: 284 only, 2005.
|
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|
|
[PubMed: 16098019]
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|
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[Full Text: https://doi.org/10.1111/j.1399-0004.2005.0485a.x]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Biesecker, L. G.
|
|
<strong>What you can learn from one gene: GLI3.</strong>
|
|
J. Med. Genet. 43: 465-469, 2006.
|
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|
|
|
[PubMed: 16740916]
|
|
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|
|
[Full Text: https://doi.org/10.1136/jmg.2004.029181]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Biesecker, L. G.
|
|
<strong>The Grieg polysyndactyly syndrome.</strong>
|
|
Orphanet J. Rare Dis. 3: 10, 2008. Note: Electronic Article.
|
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|
|
|
|
[PubMed: 18435847]
|
|
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|
|
[Full Text: https://doi.org/10.1186/1750-1172-3-10]
|
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Bose, J., Grotewold, L., Ruther, U.
|
|
<strong>Pallister-Hall syndrome phenotype in mice mutant for Gli3.</strong>
|
|
Hum. Molec. Genet. 11: 1129-1135, 2002.
|
|
|
|
|
|
[PubMed: 11978771]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/11.9.1129]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brueton, L., Huson, S. M., Winter, R. M., Williamson, R.
|
|
<strong>Chromosomal localisation of a developmental gene in man: direct DNA analysis demonstrates that Greig cephalopolysyndactyly maps to 7p13.</strong>
|
|
Am. J. Med. Genet. 31: 799-804, 1988.
|
|
|
|
|
|
[PubMed: 3239571]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1320310412]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Craig, D. W., Itty, A., Panganiban, C., Szelinger, S., Kruer, M. C., Sekar, A., Reiman, D., Narayanan, V., Stephan, D. A., Kerrigan, J. F.
|
|
<strong>Identification of somatic chromosomal abnormalities in hypothalamic hamartoma tissue at the GLI3 locus.</strong>
|
|
Am. J. Hum. Genet. 82: 366-374, 2008.
|
|
|
|
|
|
[PubMed: 18252217]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2007.10.006]
|
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|
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Debeer, P., Peeters, H., Driess, S., De Smet, L., Freese, K., Matthijs, G., Bornholdt, D., Devriendt, K., Grzeschik, K.-H., Fryns, J.-P., Kalff-Suske, M.
|
|
<strong>Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations.</strong>
|
|
Am. J. Med. Genet. 120A: 49-58, 2003.
|
|
|
|
|
|
[PubMed: 12794692]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.20018]
|
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|
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</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Demurger, F., Ichkou, A., Mougou-Zerelli, S., Le Merrer, M., Goudefroye, G., Delezoide, A.-L., Quelin, C., Manouvrier, S., Baujat, G., Fradin, M., Pasquier, L., Megarbane, A., and 40 others.
|
|
<strong>New insights into genotype-phenotype correlation for GLI3 mutations.</strong>
|
|
Europ. J. Hum. Genet. 23: 92-102, 2015.
|
|
|
|
|
|
[PubMed: 24736735]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ejhg.2014.62]
|
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|
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</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
El Mouatani, A., Van Winckel, G., Zaafrane-Khachnaoui, K., Whalen, S., Achaiaa, A., Kaltenbach, S., Superti-Furga, A., Vekemans, M., Fodstad, H., Giuliano, F., Attie-Bitach, T.
|
|
<strong>Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly.</strong>
|
|
Am. J. Med. Genet. 185A: 3831-3837, 2021.
|
|
|
|
|
|
[PubMed: 34296525]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.62426]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Elson, E., Perveen, R., Donnai, D., Wall, S., Black, G. C. M.
|
|
<strong>De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models.</strong>
|
|
J. Med. Genet. 39: 804-806, 2002.
|
|
|
|
|
|
[PubMed: 12414818]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.39.11.804]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fujioka, H., Ariga, T., Horiuchi, K., Otsu, M., Igawa, H., Kawashima, K., Yamamoto, Y., Sugihara, T., Sakiyama, Y.
|
|
<strong>Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I.</strong>
|
|
Clin. Genet. 67: 429-433, 2005.
|
|
|
|
|
|
[PubMed: 15811011]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2005.00431.x]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Fujioka, H., Ariga, T.
|
|
<strong>Response to Biesecker and Johnston. (Letter)</strong>
|
|
Clin. Genet. 68: 285 only, 2005.
|
|
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Ada Hamosh - updated : 02/01/2024<br>Bao Lige - updated : 12/12/2022<br>Bao Lige - updated : 12/01/2022<br>Ada Hamosh - updated : 04/19/2018<br>Ada Hamosh - updated : 04/16/2018<br>Patricia A. Hartz - updated : 2/26/2016<br>Ingrid M. Wentzensen - updated : 4/21/2015<br>George E. Tiller - updated : 9/26/2013<br>Marla J. F. O'Neill - updated : 2/11/2013<br>Ada Hamosh - updated : 1/14/2013<br>Ada Hamosh - updated : 5/24/2012<br>Cassandra L. Kniffin - updated : 10/27/2010<br>Patricia A. Hartz - updated : 10/5/2009<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Carol A. Bocchini - updated : 2/10/2009<br>Cassandra L. Kniffin - updated : 1/12/2009<br>Victor A. McKusick - updated : 3/31/2008<br>Cassandra L. Kniffin - updated : 10/12/2006<br>Victor A. McKusick - updated : 7/5/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Ada Hamosh - updated : 8/18/2005<br>Marla J. F. O'Neill - updated : 6/24/2005<br>Victor A. McKusick - updated : 3/11/2005<br>Victor A. McKusick - updated : 1/10/2005<br>Victor A. McKusick - updated : 5/4/2004<br>Victor A. McKusick - updated : 6/23/2003<br>Victor A. McKusick - updated : 3/25/2003<br>George E. Tiller - updated : 12/17/2002<br>Ada Hamosh - updated : 11/19/2002<br>Ada Hamosh - updated : 9/13/2002<br>Stylianos E. Antonarakis - updated : 4/5/2000<br>Victor A. McKusick - updated : 2/25/2000<br>Victor A. McKusick - updated : 10/28/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Victor A. McKusick - updated : 4/20/1999<br>Ada Hamosh - updated : 4/9/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 10/24/1997<br>Victor A. McKusick - updated : 3/2/1997
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Victor A. McKusick : 10/6/1988
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