4065 lines
338 KiB
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4065 lines
338 KiB
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- *139311 - GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-ACTIVATING ACTIVITY POLYPEPTIDE O; GNAO1
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*139311</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#description">Description</a>
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#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>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/139311">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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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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=ENSG00000087258;t=ENST00000262493" 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=2775" 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=139311" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000087258;t=ENST00000262493" 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_020988,NM_138736,XM_011523003,XR_007064866" 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_020988" 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=139311" 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=00757&isoform_id=00757_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/GNAO1" 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/183439,232133,386750,5420155,10567816,20147681,20147683,34190601,50949599,119603255,119603256,162461738,193786318,194380768,767989736,1005405643,2104758951,2462548504" 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/P09471" 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=2775" 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=ENSG00000087258;t=ENST00000262493" 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=GNAO1" 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=GNAO1" 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+2775" 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/GNAO1" 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:2775" 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/2775" 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=chr16&hgg_gene=ENST00000262493.12&hgg_start=56191489&hgg_end=56357444&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:4389" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4389" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=139311[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=139311[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/GNAO1/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/ENSG00000087258" 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=GNAO1" 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=GNAO1" 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=GNAO1" 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=GNAO1&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/PA28771" 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:4389" 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/FBgn0001122.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:95775" 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/GNAO1#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:95775" 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/2775/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=2775" 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=WBGene00001648;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-040426-1693" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2775" 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=GNAO1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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139311
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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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GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-ACTIVATING ACTIVITY POLYPEPTIDE O; GNAO1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
Go, ALPHA SUBUNIT<br />
|
|
GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-'OTHER'; GNAO<br />
|
|
G-ALPHA-o
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GNAO1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GNAO1</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/16/450?start=-3&limit=10&highlight=450">16q13</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:56191489-56357444&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'})">16:56,191,489-56,357,444</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615473,617493" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/450?start=-3&limit=10&highlight=450">
|
|
16q13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 17
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615473"> 615473 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Neurodevelopmental disorder with involuntary movements
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/617493"> 617493 </a>
|
|
|
|
</span>
|
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</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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</tbody>
|
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</table>
|
|
</div>
|
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</div>
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<p>The GNAO1 gene encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins), a large family of signal-transducing molecules. G proteins are composed of alpha, beta, and gamma subunits. Members of the G protein family have been characterized most extensively on the basis of the alpha subunit, which binds guanine nucleotide, is capable of hydrolyzing GTP, and interacts with specific receptor and effector molecules. In addition to the inhibitory G proteins, Gi (<a href="/entry/139310">139310</a>), and the stimulatory G proteins, Gs (<a href="/entry/139320">139320</a>), a Go protein has been described; 'o' means 'other.' The Go heterotrimer is abundant in brain and has been found also in the cardiac atria (summary by <a href="#16" class="mim-tip-reference" title="Strathmann, M., Wilkie, T. M., Simon, M. I. <strong>Alternative splicing produces transcripts encoding two forms of the alpha subunit of GTP-binding protein G(o).</strong> Proc. Nat. Acad. Sci. 87: 6477-6481, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1697681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1697681</a>] [<a href="https://doi.org/10.1073/pnas.87.17.6477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1697681">Strathmann et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1697681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#16" class="mim-tip-reference" title="Strathmann, M., Wilkie, T. M., Simon, M. I. <strong>Alternative splicing produces transcripts encoding two forms of the alpha subunit of GTP-binding protein G(o).</strong> Proc. Nat. Acad. Sci. 87: 6477-6481, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1697681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1697681</a>] [<a href="https://doi.org/10.1073/pnas.87.17.6477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1697681">Strathmann et al. (1990)</a> isolated cDNA clones encoding 2 forms of the Go-alpha subunit from a mouse brain library. These appear to be the products of alternative splicing. <a href="#18" class="mim-tip-reference" title="Tsukamoto, T., Toyama, R., Itoh, H., Kozasa, T., Matsuoka, M., Kaziro, Y. <strong>Structure of the human gene and two rat cDNAs encoding the alpha chain of GTP-binding regulatory protein G(o): two different mRNAs are generated by alternative splicing.</strong> Proc. Nat. Acad. Sci. 88: 2974-2978, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1901650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1901650</a>] [<a href="https://doi.org/10.1073/pnas.88.8.2974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1901650">Tsukamoto et al. (1991)</a> likewise concluded that 2 different Go-alpha mRNAs may be generated by alternative splicing of a single gene. Go-alpha has been implicated in ion channel regulation. Some tissues contain multiple Go-alpha mRNAs of various sizes that differ in the 3-prime untranslated regions (UTRs). <a href="#12" class="mim-tip-reference" title="Murtagh, J. J., Jr., Eddy, R., Shows, T. B., Moss, J., Vaughan, M. <strong>Different forms of Go alpha mRNA arise by alternative splicing of transcripts from a single gene on human chromosome 16.</strong> Molec. Cell. Biol. 11: 1146-1155, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1899283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1899283</a>] [<a href="https://doi.org/10.1128/mcb.11.2.1146-1155.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1899283">Murtagh et al. (1991)</a> concluded that the Go-alpha mRNAs with different 3-prime UTRs arise by alternative splicing of transcripts from a single gene. The UTRs were shown to exhibit a high degree of interspecies conservation and may play a role in regulation of Go-alpha expression during differentiation or in specific tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1899283+1901650+1697681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#12" class="mim-tip-reference" title="Murtagh, J. J., Jr., Eddy, R., Shows, T. B., Moss, J., Vaughan, M. <strong>Different forms of Go alpha mRNA arise by alternative splicing of transcripts from a single gene on human chromosome 16.</strong> Molec. Cell. Biol. 11: 1146-1155, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1899283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1899283</a>] [<a href="https://doi.org/10.1128/mcb.11.2.1146-1155.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1899283">Murtagh et al. (1991)</a> assigned the GNAO gene to chromosome 16 by Southern blot analysis of human-mouse somatic cell hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1899283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 10/21/2020."None>Stumpf (2020)</a> mapped the GNAO1 gene to chromosome 16q13 based on an alignment of the GNAO1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC030027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC030027</a>) with the genomic sequence (GRCh38).</p><p>By study of an interspecific backcross with restriction fragment length variants (RFLVs), <a href="#20" class="mim-tip-reference" title="Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X.-N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I., Jenkins, N. A., Copeland, N. G. <strong>Evolution of the mammalian G protein alpha subunit multigene family.</strong> Nature Genet. 1: 85-91, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302014</a>] [<a href="https://doi.org/10.1038/ng0592-85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302014">Wilkie et al. (1992)</a> showed that the Gnao gene is located on mouse chromosome 8, where it is very tightly linked to the metallothionein gene (MT1; <a href="/entry/156350">156350</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a bacterial expression system, <a href="#10" class="mim-tip-reference" title="Lan, K.-L., Sarvazyan, N. A., Taussig, R., Mackenzie, R. G., DiBello, P. R., Dohlman, H. G., Neubig, R. R. <strong>A point mutation in G-alpha-o and G-alpha-i1 blocks interaction with regulator of G protein signaling proteins.</strong> J. Biol. Chem. 273: 12794-12797, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9582306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9582306</a>] [<a href="https://doi.org/10.1074/jbc.273.21.12794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9582306">Lan et al. (1998)</a> found that point mutations in the Gnai1 and Gnao1 genes, G183S and G184S, respectively, resulted in resistance to regulators of G protein signaling proteins (RGS). The mutant G-alpha proteins showed significantly decreased affinity for RGS4 (<a href="/entry/602516">602516</a>) and RGS7 (<a href="/entry/602517">602517</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9582306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kroll, S. D., Chen, J., De Vivo, M., Carty, D. J., Buku, A., Premont, R. T., Iyengar, R. <strong>The Q205L G(o)-alpha subunit expressed in NIH-3T3 cells induces transformation.</strong> J. Biol. Chem. 267: 23183-23188, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1429665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1429665</a>]" pmid="1429665">Kroll et al. (1992)</a> demonstrated that expression of Q205L Go-alpha, which lacks guanosine triphosphatase activity in NIH 3T3 cells, results in transformation in a phospholipase C (see <a href="/entry/600220">600220</a>)-independent manner. <a href="#14" class="mim-tip-reference" title="Ram, P. T., Horvath, C. M., Iyengar, R. <strong>Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L G-alpha(o) protein.</strong> Science 287: 142-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615050</a>] [<a href="https://doi.org/10.1126/science.287.5450.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10615050">Ram et al. (2000)</a> studied the roles of the MAP kinases (see MAPK1, <a href="/entry/176948">176948</a>) and STAT3 (<a href="/entry/102582">102582</a>) in transformation of NIH 3T3 cells by Q205L Go-alpha. Expression of Q205L Go-alpha in NIH 3T3 cells activated STAT3 but not MAPK1 or -2. Coexpression of dominant-negative STAT3 inhibited Q205L Go-alpha-induced transformation of NIH 3T3 cells and activation of endogenous STAT3. Furthermore, Q205L Go-alpha expression increased activity of the c-Src (<a href="/entry/190090">190090</a>), and the Q205L Go-alpha-induced activation of STAT3 was blocked by expression of CSK (<a href="/entry/124095">124095</a>), which inactivates c-Src. <a href="#14" class="mim-tip-reference" title="Ram, P. T., Horvath, C. M., Iyengar, R. <strong>Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L G-alpha(o) protein.</strong> Science 287: 142-144, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615050</a>] [<a href="https://doi.org/10.1126/science.287.5450.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10615050">Ram et al. (2000)</a> concluded that STAT3 can function as a downstream effector for Q205L Go-alpha and mediate its biologic effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1429665+10615050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., and 20 others. <strong>Diverse somatic mutation patterns and pathway alterations in human cancers.</strong> Nature 466: 869-873, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20668451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20668451</a>] [<a href="https://doi.org/10.1038/nature09208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20668451">Kan et al. (2010)</a> reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Integrated analysis of somatic mutations and copy number alterations identified 35 significantly altered genes including GNAS (see <a href="/entry/139320">139320</a>), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 and mutant MAP2K4 (<a href="/entry/601335">601335</a>) in oncogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20668451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Developmental and Epileptic Encephalopathy 17</em></strong></p><p>
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In 4 unrelated girls with developmental and epileptic encephalopathy-17 (DEE17; <a href="/entry/615473">615473</a>), <a href="#13" class="mim-tip-reference" title="Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. <strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong> Am. J. Hum. Genet. 93: 496-505, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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.2013.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993195">Nakamura et al. (2013)</a> identified 4 different de novo heterozygous mutations in the GNAO1 gene (<a href="#0001">139311.0001</a>-<a href="#0004">139311.0004</a>). The mutations in the first 2 patients were found by whole-exome sequencing, and the mutations in the second 2 patients were found by direct sequencing of the GNAO1 gene in 367 individuals with epileptic encephalopathy. Three patients had onset of intractable tonic seizures in the first weeks of life associated with suppression-burst pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome. The fourth patient presented with opisthotonic posturing and developmental delay at age 7 months. All had severely delayed psychomotor development, with lack of sitting, no speech, and head control only in 1 patient. One child died at age 11 months. One patient showed dystonia and another had severe chorea and athetosis. Brain MRI was abnormal in 3 patients, showing cerebral atrophy, delayed myelination, and thin corpus callosum. In vitro functional expression studies showed that 3 of the mutations impaired normal protein localization in the plasma membrane, and electrophysiologic analysis showed that 3 of the mutations caused decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to wildtype. The findings suggested that aberrant GNAO1 signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Neurodevelopmental Disorder With Involuntary Movements</em></strong></p><p>
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In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#9" class="mim-tip-reference" title="Kulkarni, N., Tang, S., Bhardwaj, R., Bernes, S., Grebe, T. A. <strong>Progressive movement disorder in brothers carrying a GNAO1 mutation responsive to deep brain stimulation.</strong> J. Child. Neurol. 31: 211-214, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060304</a>] [<a href="https://doi.org/10.1177/0883073815587945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26060304">Kulkarni et al. (2016)</a> identified a de novo heterozygous missense mutation in the GNAO1 gene (R209H; <a href="#0005">139311.0005</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in 1 of them. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. Using exome sequencing, <a href="#11" class="mim-tip-reference" title="Menke, L. A., Engelen, M., Alders, M., Odekerken, V. J. J., Baas, F., Cobben, J. M. <strong>Recurrent GNAO1 mutations associated with developmental delay and a movement disorder.</strong> J. Child Neurol. 31: 1598-1601, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>] [<a href="https://doi.org/10.1177/0883073816666474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27625011">Menke et al. (2016)</a> identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27625011+26060304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2 unrelated patients with NEDIM, <a href="#15" class="mim-tip-reference" title="Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. <strong>Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.</strong> Europ. J. Hum. Genet. 24: 129-134, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25966631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25966631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25966631[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.2015.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25966631">Saitsu et al. (2016)</a> identified 2 different de novo heterozygous missense mutations in the GNAO1 gene (R209C, <a href="#0006">139311.0006</a> and E246K, <a href="#0007">139311.0007</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that they would result in adverse effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25966631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6 patients, including 2 sibs, with NEDIM, <a href="#1" class="mim-tip-reference" title="Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. <strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong> Pediat. Neurol. 59: 81-84, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27068059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27068059</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2016.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27068059">Ananth et al. (2016)</a> identified de novo heterozygous missense mutations in the GNAO1 gene: E246K was found in 4 patients, R209H was found in 1 patient, and R209G (<a href="#0008">139311.0008</a>) was found in 1 patient. The mutations were found by whole-exome sequencing. Functional studies of the variants and studies of patient cells were not performed. None of the patients had seizures, suggesting that these mutations may be specific to the movement disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27068059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6 patients with NEDIM, <a href="#2" class="mim-tip-reference" title="Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others. <strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong> Neurol. Genet. 3: e143, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28357411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28357411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28357411[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/10.1212/NXG.0000000000000143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28357411">Danti et al. (2017)</a> identified de novo heterozygous mutations in the GNAO1 gene (see, e.g., R209C, <a href="#0006">139311.0006</a> and E246G, <a href="#0009">139311.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28357411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 unrelated boys with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#11" class="mim-tip-reference" title="Menke, L. A., Engelen, M., Alders, M., Odekerken, V. J. J., Baas, F., Cobben, J. M. <strong>Recurrent GNAO1 mutations associated with developmental delay and a movement disorder.</strong> J. Child Neurol. 31: 1598-1601, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>] [<a href="https://doi.org/10.1177/0883073816666474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27625011">Menke et al. (2016)</a> identified de novo heterozygous missense mutations affecting codon 209 in the GNAO1 gene (R209H, <a href="#0005">139311.0005</a> and R209L). In a review of 26 published patients with GNAO1 mutations, <a href="#11" class="mim-tip-reference" title="Menke, L. A., Engelen, M., Alders, M., Odekerken, V. J. J., Baas, F., Cobben, J. M. <strong>Recurrent GNAO1 mutations associated with developmental delay and a movement disorder.</strong> J. Child Neurol. 31: 1598-1601, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>] [<a href="https://doi.org/10.1177/0883073816666474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27625011">Menke et al. (2016)</a> found that those with mutations affecting codon 209 (e.g., R209C, R209H, R209G) or 246 (E246K; <a href="#0007">139311.0007</a>) had developmental delay with a hyperkinetic movement disorder but without seizures. These mutations were recurrent de novo mutations, probably related to both being part of CpG dinucleotides, which are known to be vulnerable to spontaneous deamination. In contrast, patients with mutations affecting other residues had the more severe phenotype of infantile-onset epileptic encephalopathy (DEE17). <a href="#11" class="mim-tip-reference" title="Menke, L. A., Engelen, M., Alders, M., Odekerken, V. J. J., Baas, F., Cobben, J. M. <strong>Recurrent GNAO1 mutations associated with developmental delay and a movement disorder.</strong> J. Child Neurol. 31: 1598-1601, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>] [<a href="https://doi.org/10.1177/0883073816666474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27625011">Menke et al. (2016)</a> noted that affected sib pairs with the same de novo mutation had been reported, and they estimated a recurrence risk of 5 to 15% after 1 affected child with GNAO1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27625011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Feng, H., Sjogren, B., Karaj, B., Shaw, V., Gezer, A., Neugib, R. R. <strong>Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.</strong> Neurology 89: 762-770, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28747448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28747448</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28747448">Feng et al. (2017)</a> performed functional and biochemical studies of 15 de novo GNAO1 mutations. Western blot analysis of HEK293 cells showed that most of the mutations resulted in decreased protein levels. Three variants affecting Arg209 showed normal protein expression, as did G184S. Functional studies assessing GNAO1-dependent cAMP inhibition when coexpressed with an adrenergic receptor showed that 9 of the mutations resulted in a loss of function (LOF), usually associated with significantly decreased protein levels, whereas 6 had normal or even gain-of-function (GOF) behavior compared to wildtype. The LOF variants were associated with DEE17, whereas the normal or GOF variants were associated with movement disorders with or without seizures. Molecular modeling also showed some correlation with the location of the mutations: GOF mutations were near G184S and close to the ribose and phosphate moieties of the bound GDP, whereas LOF mutations were more broadly scattered throughout the GTPase domain and may destabilize protein folding or stability consistent with their markedly reduced expression levels. <a href="#3" class="mim-tip-reference" title="Feng, H., Sjogren, B., Karaj, B., Shaw, V., Gezer, A., Neugib, R. R. <strong>Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.</strong> Neurology 89: 762-770, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28747448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28747448</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28747448">Feng et al. (2017)</a> discussed the possible therapeutic implications of their findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28747448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#5" class="mim-tip-reference" title="Jiang, M., Gold, M. S., Boulay, G., Spicher, K., Peyton, M., Brabet, P., Srinivasan, Y., Rudolph, U., Ellison, G., Birnbaumer, L. <strong>Multiple neurological abnormalities in mice deficient in the G protein G(o).</strong> Proc. Nat. Acad. Sci. 95: 3269-3274, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9501252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9501252</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9501252[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.95.6.3269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9501252">Jiang et al. (1998)</a> disrupted the Gnao1 gene in mice by homologous recombination; median survival was only 7 weeks. At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol was unaffected, but opioid receptor-mediated inhibition of calcium channel currents was decreased by 30%. In 25% of the homozygous mutant cells examined, the calcium channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alpha-o was not accompanied by appearance of significant amounts of active free beta-gamma dimers. Homozygous mutant mice were hyperalgesic and displayed a severe motor control impairment. Despite this problem, homozygous mutant mice were hyperactive and exhibited a turning behavior that had them running in circles for hours on end both in cages and in open-field tests. Except for one, all mutant mice turned counterclockwise. These results indicate that Go plays a major role in motor control, motor behavior, and pain perception and predict involvement of Go in calcium channel regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9501252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To analyze the function of Go-alpha in the heart, <a href="#19" class="mim-tip-reference" title="Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C. <strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong> Proc. Nat. Acad. Sci. 94: 1727-2732, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050846[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.94.5.1727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9050846">Valenzuela et al. (1997)</a> generated knockout mice lacking both forms of Go-alpha by homologous recombination and studied the muscarinic regulation of calcium channels in cardiac muscles in Go-alpha -/- mice and controls. There was no difference in the effect of isoproterenol on the L-type voltage-dependent calcium channel (<a href="/entry/114205">114205</a>) in ventricular myocytes of both groups, but the inhibitory effect of carbamylcholine was almost completely abolished in the Go-alpha -/- group. This demonstrated that, in the heart, Go-alpha is specifically required for transmission of signals from the muscarinic receptor to the L-type voltage-dependent calcium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9050846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Go-alpha has been implicated as the primary signaling element coupling alpha-2-adrenergic receptors to N-type calcium channels in sympathetic neurons. <a href="#4" class="mim-tip-reference" title="Jeong, S.-W., Ikeda, S. R. <strong>Endogenous regulator of G-protein signaling proteins modify N-type calcium channel modulation in rat sympathetic neurons.</strong> J. Neurosci. 20: 4489-4496, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10844018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10844018</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.20-12-04489.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10844018">Jeong and Ikeda (2000)</a> found that in rat neurons expressing a Go-alpha subunit resistant to pertussis toxin and resistant to regulators of G protein signaling proteins, norepinephrine-induced calcium current inhibition was shifted to lower concentrations. In addition to an increase in agonist potency, the expression of the resistant Go-alpha subunit retarded the current recovery after agonist removal. The data suggested that endogenous RGS proteins contribute to calcium channel modulation by regulating agonist potency and kinetics of G protein-mediated signaling in neuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10844018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kehrl, J. M., Sahaya, K., Dalton, H. M., Charbeneau, R. A., Kohut, K. T., Gilbert, K., Pelz, M. C., Parent, J., Neubig, R. R. <strong>Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?</strong> Mammalian Genome 25: 202-210, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700286</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24700286[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/10.1007/s00335-014-9509-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700286">Kehrl et al. (2014)</a> found that mutant mice heterozygous for a G184S mutation in the Gnao1 gene died in the perinatal period or early in life due to sudden death associated with severe seizures and/or increased frequency of interictal epileptiform discharges. Homozygous mutant mice were essentially nonviable. Heterozygous mice showed enhanced sensitivity to seizure kindling with a GABA antagonist compared to controls. Heterozygous knockout mice, representing a loss of function, did not show such a phenotype, suggesting that the G184S mutation results in a gain of function. <a href="#7" class="mim-tip-reference" title="Kehrl, J. M., Sahaya, K., Dalton, H. M., Charbeneau, R. A., Kohut, K. T., Gilbert, K., Pelz, M. C., Parent, J., Neubig, R. R. <strong>Gain-of-function mutation in Gnao1: a murine model of epileptiform encephalopathy (EIEE17)?</strong> Mammalian Genome 25: 202-210, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700286</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24700286[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/10.1007/s00335-014-9509-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24700286">Kehrl et al. (2014)</a> noted that several studies have shown that the G184S allele results in a gain of function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24700286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="/allelicVariants/139311" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=139311[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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">rs587777054 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777054;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=rs587777054" 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=rs587777054" 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=RCV000056405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056405</a>
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<p>In a 13-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; <a href="/entry/615473">615473</a>), <a href="#13" class="mim-tip-reference" title="Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. <strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong> Am. J. Hum. Genet. 93: 496-505, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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.2013.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993195">Nakamura et al. (2013)</a> identified a de novo heterozygous c.836T-A transversion in the GNAO1 gene, resulting in an ile279-to-asn (I279N) substitution. The mutation specifically affected GNAO1 transcript variant 1. The mutation was found by whole-exome sequencing and was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein had some abnormal cytoplasmic localization. The patient had onset of seizures on day 4 of life. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777055 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777055;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=rs587777055" 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=rs587777055" 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=RCV000056406 OR RCV002281559" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056406, RCV002281559" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056406...</a>
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<p>In a 4-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; <a href="/entry/615473">615473</a>), <a href="#13" class="mim-tip-reference" title="Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. <strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong> Am. J. Hum. Genet. 93: 496-505, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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.2013.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993195">Nakamura et al. (2013)</a> identified a de novo heterozygous c.521A-G transition in the GNAO1 gene, resulting in an asp174-to-gly (D174G) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was determined to be somatic mosaic by deep sequencing of PCR products of DNA from blood and saliva samples from the patient and her parents. The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein had some abnormal cytoplasmic localization. Electrophysiologic studies in N-type calcium channels indicated that the mutant protein had impaired current inhibition after norepinephrine application compared to wildtype, suggesting that the mutation could hamper GNAO1-mediated signaling. The patient had onset of seizures at 29 days of age. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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">rs587777056 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777056;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=rs587777056" 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=rs587777056" 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=RCV000056407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056407</a>
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<p>In a female infant with developmental and epileptic encephalopathy-17 (DEE17; <a href="/entry/615473">615473</a>), <a href="#13" class="mim-tip-reference" title="Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. <strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong> Am. J. Hum. Genet. 93: 496-505, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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.2013.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993195">Nakamura et al. (2013)</a> identified a de novo identified a de novo heterozygous 21-bp deletion (c.572_592del), resulting in an in-frame deletion of 7 residues (Thr191_Phe197). The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein accumulated in the cytoplasmic compartment instead of being normally located to the cell periphery. Electrophysiologic studies in N-type calcium channels showed that the mutant protein had increased calcium-current density compared to wildtype before norepinephrine application, and showed only a mild reduction in calcium current compared to wildtype after application of norepinephrine. The findings suggested that the mutation could hamper GNAO1-mediated signaling. The patient had onset of intractable seizures at 2 weeks of age. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. She died at 11 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000056408 OR RCV000255097 OR RCV000468248 OR RCV000762963 OR RCV001252685 OR RCV001256978 OR RCV001814039 OR RCV003421966" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056408, RCV000255097, RCV000468248, RCV000762963, RCV001252685, RCV001256978, RCV001814039, RCV003421966" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056408...</a>
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<p>In an 8-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; <a href="/entry/615473">615473</a>), <a href="#13" class="mim-tip-reference" title="Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others. <strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong> Am. J. Hum. Genet. 93: 496-505, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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.2013.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993195">Nakamura et al. (2013)</a> identified a de novo heterozygous c.607G-A transition in the GNAO1 gene, resulting in a gly203-to-arg (G203R) substitution in the highly conserved switch II region that is responsible for activation of downstream effectors. The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein localized normally to the cell periphery. However, electrophysiologic studies in N-type calcium channels indicated that the similar G203T mutant protein had impaired current inhibition after norepinephrine application compared to wildtype, suggesting that the mutation could hamper GNAO1-mediated signaling. The patient showed opisthotonic posturing at 7 months of age. She later developed severe chorea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 14-month-old girl with DEE17, <a href="#15" class="mim-tip-reference" title="Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. <strong>Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.</strong> Europ. J. Hum. Genet. 24: 129-134, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25966631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25966631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25966631[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.2015.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25966631">Saitsu et al. (2016)</a> identified a de novo heterozygous G203R mutation in the GNAO1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. The patient developed seizures on the seventh day of life. She later developed severe chorea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25966631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Feng, H., Sjogren, B., Karaj, B., Shaw, V., Gezer, A., Neugib, R. R. <strong>Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.</strong> Neurology 89: 762-770, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28747448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28747448</a>] [<a href="https://doi.org/10.1212/WNL.0000000000004262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28747448">Feng et al. (2017)</a> found that the G203R variant resulted in a gain-of-function effect in a cAMP inhibition assay. The authors noted that the previously reported patients with this variant had a slightly different phenotype from classic DEE17, showing a prominent motor component. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28747448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#9" class="mim-tip-reference" title="Kulkarni, N., Tang, S., Bhardwaj, R., Bernes, S., Grebe, T. A. <strong>Progressive movement disorder in brothers carrying a GNAO1 mutation responsive to deep brain stimulation.</strong> J. Child. Neurol. 31: 211-214, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26060304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26060304</a>] [<a href="https://doi.org/10.1177/0883073815587945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26060304">Kulkarni et al. (2016)</a> identified a de novo heterozygous c.626G-A transition in exon 6 of the GNAO1 gene, resulting in an arg209-to-his (R209H) substitution at a conserved residue in the highly conserved switch II region, which activates downstream effectors upon GTP binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in one of them. The mutation was filtered against the dbSNP and 1000 Genomes Project databases and was not found in the Exome Sequencing Project database. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26060304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 exome sequencing, <a href="#11" class="mim-tip-reference" title="Menke, L. A., Engelen, M., Alders, M., Odekerken, V. J. J., Baas, F., Cobben, J. M. <strong>Recurrent GNAO1 mutations associated with developmental delay and a movement disorder.</strong> J. Child Neurol. 31: 1598-1601, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>] [<a href="https://doi.org/10.1177/0883073816666474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27625011">Menke et al. (2016)</a> identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27625011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 16-year-old boy with NEDIM, <a href="#1" class="mim-tip-reference" title="Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. <strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong> Pediat. Neurol. 59: 81-84, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27068059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27068059</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2016.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27068059">Ananth et al. (2016)</a> identified a de novo heterozygous R209H mutation in the GNAO1 gene. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27068059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039494;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=rs886039494" 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=rs886039494" 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=RCV000256155 OR RCV000475848 OR RCV000490628 OR RCV000622320 OR RCV001003612 OR RCV001775107 OR RCV003401217" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000256155, RCV000475848, RCV000490628, RCV000622320, RCV001003612, RCV001775107, RCV003401217" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000256155...</a>
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<p>In an 18-year-old female with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#15" class="mim-tip-reference" title="Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. <strong>Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.</strong> Europ. J. Hum. Genet. 24: 129-134, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25966631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25966631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25966631[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.2015.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25966631">Saitsu et al. (2016)</a> identified a de novo heterozygous c.625C-T transition (c.625C-T, NM_020988.2) in exon 6 of the GNAO1 gene, resulting in an arg209-to-cys (R209C) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would destabilize the G-alpha-containing complexes mainly in GTP-bound active state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25966631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others. <strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong> Neurol. Genet. 3: e143, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28357411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28357411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28357411[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/10.1212/NXG.0000000000000143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28357411">Danti et al. (2017)</a> identified a de novo heterozygous R209C mutation in 2 unrelated patients with NEDIM. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="#2" class="mim-tip-reference" title="Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others. <strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong> Neurol. Genet. 3: e143, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28357411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28357411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28357411[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/10.1212/NXG.0000000000000143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28357411">Danti et al. (2017)</a> noted that the R209C mutation occurs in the switch II domain, which is important for regulation of downstream signaling. This residue (R209) is a mutational hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28357411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044951 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044951;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=rs797044951" 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=rs797044951" 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=RCV000190803 OR RCV000254701 OR RCV000490631 OR RCV001580372 OR RCV001808530 OR RCV001814097 OR RCV001857676 OR RCV003996903" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190803, RCV000254701, RCV000490631, RCV001580372, RCV001808530, RCV001814097, RCV001857676, RCV003996903" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190803...</a>
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<p>In a 13-year-old girl with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#15" class="mim-tip-reference" title="Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others. <strong>Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.</strong> Europ. J. Hum. Genet. 24: 129-134, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25966631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25966631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25966631[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.2015.92" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25966631">Saitsu et al. (2016)</a> identified a de novo heterozygous c.736G-A transition (c.736G-A, NM_020988.2) in exon 7 of the GNAO1 gene, resulting in a glu246-to-lys (E246K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would destabilize the G-alpha-containing complexes mainly in GTP-bound active state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25966631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4 patients, including 2 sibs, with NEDIM, <a href="#1" class="mim-tip-reference" title="Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. <strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong> Pediat. Neurol. 59: 81-84, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27068059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27068059</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2016.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27068059">Ananth et al. (2016)</a> identified a de novo heterozygous E246K mutation. The mutations were found by whole-exome sequencing. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27068059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886039494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039494;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=rs886039494" 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=rs886039494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4-year-old girl with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#1" class="mim-tip-reference" title="Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. <strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong> Pediat. Neurol. 59: 81-84, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27068059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27068059</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2016.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27068059">Ananth et al. (2016)</a> identified a de novo heterozygous c.625C-G transversion in the GNAO1 gene, resulting in an arg209-to-gly (R209G) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27068059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</strong>
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GNAO1, GLU246GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1114167431 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1114167431;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=rs1114167431" 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=rs1114167431" 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=RCV000490634" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000490634" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000490634</a>
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<p>In a patient with neurodevelopmental disorder with involuntary movements (NEDIM; <a href="/entry/617493">617493</a>), <a href="#2" class="mim-tip-reference" title="Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others. <strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong> Neurol. Genet. 3: e143, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28357411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28357411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28357411[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/10.1212/NXG.0000000000000143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28357411">Danti et al. (2017)</a> identified a de novo heterozygous c.737A-G transition in the GNAO1 gene, resulting in a glu246-to-gly (E246G) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28357411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A.
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<strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong>
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Pediat. Neurol. 59: 81-84, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27068059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27068059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27068059" 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.pediatrneurol.2016.02.018" target="_blank">Full Text</a>]
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Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others.
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<strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong>
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Neurol. Genet. 3: e143, 2017. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28357411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28357411</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28357411[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=28357411" 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/10.1212/NXG.0000000000000143" target="_blank">Full Text</a>]
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Feng, H., Sjogren, B., Karaj, B., Shaw, V., Gezer, A., Neugib, R. R.
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<strong>Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations.</strong>
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[<a href="https://doi.org/10.1212/WNL.0000000000004262" target="_blank">Full Text</a>]
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Jeong, S.-W., Ikeda, S. R.
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[<a href="https://doi.org/10.1523/JNEUROSCI.20-12-04489.2000" target="_blank">Full Text</a>]
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Jiang, M., Gold, M. S., Boulay, G., Spicher, K., Peyton, M., Brabet, P., Srinivasan, Y., Rudolph, U., Ellison, G., Birnbaumer, L.
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[<a href="https://doi.org/10.1073/pnas.95.6.3269" target="_blank">Full Text</a>]
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Kan, Z., Jaiswal, B. S., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H. M., Yue, P., Haverty, P. M., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., and 20 others.
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[<a href="https://doi.org/10.1038/nature09208" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/0883073815587945" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.21.12794" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27625011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27625011</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27625011" 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/10.1177/0883073816666474" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Murtagh, J. J., Jr., Eddy, R., Shows, T. B., Moss, J., Vaughan, M.
|
|
<strong>Different forms of Go alpha mRNA arise by alternative splicing of transcripts from a single gene on human chromosome 16.</strong>
|
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Molec. Cell. Biol. 11: 1146-1155, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1899283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1899283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1899283" 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/10.1128/mcb.11.2.1146-1155.1991" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Nakamura2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others.
|
|
<strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong>
|
|
Am. J. Hum. Genet. 93: 496-505, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993195[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=23993195" 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.2013.07.014" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Ram2000" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Ram, P. T., Horvath, C. M., Iyengar, R.
|
|
<strong>Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L G-alpha(o) protein.</strong>
|
|
Science 287: 142-144, 2000.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10615050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10615050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10615050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.287.5450.142" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Saitsu2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others.
|
|
<strong>Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay.</strong>
|
|
Europ. J. Hum. Genet. 24: 129-134, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25966631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25966631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25966631[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=25966631" 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/ejhg.2015.92" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Strathmann1990" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Strathmann, M., Wilkie, T. M., Simon, M. I.
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<strong>Alternative splicing produces transcripts encoding two forms of the alpha subunit of GTP-binding protein G(o).</strong>
|
|
Proc. Nat. Acad. Sci. 87: 6477-6481, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1697681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1697681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1697681" 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.87.17.6477" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Stumpf2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 10/21/2020.
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Tsukamoto1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tsukamoto, T., Toyama, R., Itoh, H., Kozasa, T., Matsuoka, M., Kaziro, Y.
|
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<strong>Structure of the human gene and two rat cDNAs encoding the alpha chain of GTP-binding regulatory protein G(o): two different mRNAs are generated by alternative splicing.</strong>
|
|
Proc. Nat. Acad. Sci. 88: 2974-2978, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1901650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1901650</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1901650" 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.88.8.2974" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Valenzuela1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C.
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<strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong>
|
|
Proc. Nat. Acad. Sci. 94: 1727-2732, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050846</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050846[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=9050846" 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.94.5.1727" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Wilkie1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X.-N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I., Jenkins, N. A., Copeland, N. G.
|
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<strong>Evolution of the mammalian G protein alpha subunit multigene family.</strong>
|
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Nature Genet. 1: 85-91, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302014" 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/ng0592-85" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 10/21/2020
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/27/2018<br>Cassandra L. Kniffin - updated : 05/31/2017<br>Cassandra L. Kniffin - updated : 9/16/2015<br>Cassandra L. Kniffin - updated : 10/15/2013<br>Ada Hamosh - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 6/5/2006<br>Ada Hamosh - updated : 12/30/1999<br>Wilson H. Y. Lo - updated : 7/26/1999<br>Ada Hamosh - updated : 3/18/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/16/1990
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/21/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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joanna : 10/09/2020<br>carol : 03/08/2018<br>ckniffin : 02/27/2018<br>carol : 06/02/2017<br>ckniffin : 05/31/2017<br>carol : 09/18/2015<br>carol : 9/17/2015<br>ckniffin : 9/16/2015<br>carol : 10/16/2013<br>ckniffin : 10/15/2013<br>alopez : 9/23/2010<br>terry : 9/21/2010<br>carol : 6/29/2006<br>ckniffin : 6/5/2006<br>alopez : 6/13/2001<br>alopez : 12/30/1999<br>carol : 7/26/1999<br>alopez : 3/18/1999<br>alopez : 3/18/1999<br>carol : 7/2/1998<br>mark : 9/3/1997<br>carol : 7/6/1992<br>carol : 5/26/1992<br>carol : 5/19/1992<br>supermim : 3/16/1992<br>carol : 5/13/1991<br>carol : 10/16/1990
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 139311
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-ACTIVATING ACTIVITY POLYPEPTIDE O; GNAO1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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Go, ALPHA SUBUNIT<br />
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GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-'OTHER'; GNAO<br />
|
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G-ALPHA-o
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: GNAO1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
|
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<em>
|
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Cytogenetic location: 16q13
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 16:56,191,489-56,357,444 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
16q13
|
|
</span>
|
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</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 17
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615473
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Neurodevelopmental disorder with involuntary movements
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617493
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
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<span class="mim-font">
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3
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</tr>
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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The GNAO1 gene encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins), a large family of signal-transducing molecules. G proteins are composed of alpha, beta, and gamma subunits. Members of the G protein family have been characterized most extensively on the basis of the alpha subunit, which binds guanine nucleotide, is capable of hydrolyzing GTP, and interacts with specific receptor and effector molecules. In addition to the inhibitory G proteins, Gi (139310), and the stimulatory G proteins, Gs (139320), a Go protein has been described; 'o' means 'other.' The Go heterotrimer is abundant in brain and has been found also in the cardiac atria (summary by Strathmann et al., 1990). </p>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Strathmann et al. (1990) isolated cDNA clones encoding 2 forms of the Go-alpha subunit from a mouse brain library. These appear to be the products of alternative splicing. Tsukamoto et al. (1991) likewise concluded that 2 different Go-alpha mRNAs may be generated by alternative splicing of a single gene. Go-alpha has been implicated in ion channel regulation. Some tissues contain multiple Go-alpha mRNAs of various sizes that differ in the 3-prime untranslated regions (UTRs). Murtagh et al. (1991) concluded that the Go-alpha mRNAs with different 3-prime UTRs arise by alternative splicing of transcripts from a single gene. The UTRs were shown to exhibit a high degree of interspecies conservation and may play a role in regulation of Go-alpha expression during differentiation or in specific tissues. </p>
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</span>
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<div>
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<br />
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<div>
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<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>Murtagh et al. (1991) assigned the GNAO gene to chromosome 16 by Southern blot analysis of human-mouse somatic cell hybrids. </p><p>Stumpf (2020) mapped the GNAO1 gene to chromosome 16q13 based on an alignment of the GNAO1 sequence (GenBank BC030027) with the genomic sequence (GRCh38).</p><p>By study of an interspecific backcross with restriction fragment length variants (RFLVs), Wilkie et al. (1992) showed that the Gnao gene is located on mouse chromosome 8, where it is very tightly linked to the metallothionein gene (MT1; 156350). </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a bacterial expression system, Lan et al. (1998) found that point mutations in the Gnai1 and Gnao1 genes, G183S and G184S, respectively, resulted in resistance to regulators of G protein signaling proteins (RGS). The mutant G-alpha proteins showed significantly decreased affinity for RGS4 (602516) and RGS7 (602517). </p><p>Kroll et al. (1992) demonstrated that expression of Q205L Go-alpha, which lacks guanosine triphosphatase activity in NIH 3T3 cells, results in transformation in a phospholipase C (see 600220)-independent manner. Ram et al. (2000) studied the roles of the MAP kinases (see MAPK1, 176948) and STAT3 (102582) in transformation of NIH 3T3 cells by Q205L Go-alpha. Expression of Q205L Go-alpha in NIH 3T3 cells activated STAT3 but not MAPK1 or -2. Coexpression of dominant-negative STAT3 inhibited Q205L Go-alpha-induced transformation of NIH 3T3 cells and activation of endogenous STAT3. Furthermore, Q205L Go-alpha expression increased activity of the c-Src (190090), and the Q205L Go-alpha-induced activation of STAT3 was blocked by expression of CSK (124095), which inactivates c-Src. Ram et al. (2000) concluded that STAT3 can function as a downstream effector for Q205L Go-alpha and mediate its biologic effects. </p><p>Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Integrated analysis of somatic mutations and copy number alterations identified 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 and mutant MAP2K4 (601335) in oncogenesis. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Developmental and Epileptic Encephalopathy 17</em></strong></p><p>
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In 4 unrelated girls with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified 4 different de novo heterozygous mutations in the GNAO1 gene (139311.0001-139311.0004). The mutations in the first 2 patients were found by whole-exome sequencing, and the mutations in the second 2 patients were found by direct sequencing of the GNAO1 gene in 367 individuals with epileptic encephalopathy. Three patients had onset of intractable tonic seizures in the first weeks of life associated with suppression-burst pattern on EEG, consistent with a clinical diagnosis of Ohtahara syndrome. The fourth patient presented with opisthotonic posturing and developmental delay at age 7 months. All had severely delayed psychomotor development, with lack of sitting, no speech, and head control only in 1 patient. One child died at age 11 months. One patient showed dystonia and another had severe chorea and athetosis. Brain MRI was abnormal in 3 patients, showing cerebral atrophy, delayed myelination, and thin corpus callosum. In vitro functional expression studies showed that 3 of the mutations impaired normal protein localization in the plasma membrane, and electrophysiologic analysis showed that 3 of the mutations caused decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to wildtype. The findings suggested that aberrant GNAO1 signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements. </p><p><strong><em>Neurodevelopmental Disorder With Involuntary Movements</em></strong></p><p>
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In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Kulkarni et al. (2016) identified a de novo heterozygous missense mutation in the GNAO1 gene (R209H; 139311.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in 1 of them. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. Using exome sequencing, Menke et al. (2016) identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed. </p><p>In 2 unrelated patients with NEDIM, Saitsu et al. (2016) identified 2 different de novo heterozygous missense mutations in the GNAO1 gene (R209C, 139311.0006 and E246K, 139311.0007). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that they would result in adverse effects. </p><p>In 6 patients, including 2 sibs, with NEDIM, Ananth et al. (2016) identified de novo heterozygous missense mutations in the GNAO1 gene: E246K was found in 4 patients, R209H was found in 1 patient, and R209G (139311.0008) was found in 1 patient. The mutations were found by whole-exome sequencing. Functional studies of the variants and studies of patient cells were not performed. None of the patients had seizures, suggesting that these mutations may be specific to the movement disorder. </p><p>In 6 patients with NEDIM, Danti et al. (2017) identified de novo heterozygous mutations in the GNAO1 gene (see, e.g., R209C, 139311.0006 and E246G, 139311.0009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>In 2 unrelated boys with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Menke et al. (2016) identified de novo heterozygous missense mutations affecting codon 209 in the GNAO1 gene (R209H, 139311.0005 and R209L). In a review of 26 published patients with GNAO1 mutations, Menke et al. (2016) found that those with mutations affecting codon 209 (e.g., R209C, R209H, R209G) or 246 (E246K; 139311.0007) had developmental delay with a hyperkinetic movement disorder but without seizures. These mutations were recurrent de novo mutations, probably related to both being part of CpG dinucleotides, which are known to be vulnerable to spontaneous deamination. In contrast, patients with mutations affecting other residues had the more severe phenotype of infantile-onset epileptic encephalopathy (DEE17). Menke et al. (2016) noted that affected sib pairs with the same de novo mutation had been reported, and they estimated a recurrence risk of 5 to 15% after 1 affected child with GNAO1 mutations. </p><p>Feng et al. (2017) performed functional and biochemical studies of 15 de novo GNAO1 mutations. Western blot analysis of HEK293 cells showed that most of the mutations resulted in decreased protein levels. Three variants affecting Arg209 showed normal protein expression, as did G184S. Functional studies assessing GNAO1-dependent cAMP inhibition when coexpressed with an adrenergic receptor showed that 9 of the mutations resulted in a loss of function (LOF), usually associated with significantly decreased protein levels, whereas 6 had normal or even gain-of-function (GOF) behavior compared to wildtype. The LOF variants were associated with DEE17, whereas the normal or GOF variants were associated with movement disorders with or without seizures. Molecular modeling also showed some correlation with the location of the mutations: GOF mutations were near G184S and close to the ribose and phosphate moieties of the bound GDP, whereas LOF mutations were more broadly scattered throughout the GTPase domain and may destabilize protein folding or stability consistent with their markedly reduced expression levels. Feng et al. (2017) discussed the possible therapeutic implications of their findings. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jiang et al. (1998) disrupted the Gnao1 gene in mice by homologous recombination; median survival was only 7 weeks. At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol was unaffected, but opioid receptor-mediated inhibition of calcium channel currents was decreased by 30%. In 25% of the homozygous mutant cells examined, the calcium channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alpha-o was not accompanied by appearance of significant amounts of active free beta-gamma dimers. Homozygous mutant mice were hyperalgesic and displayed a severe motor control impairment. Despite this problem, homozygous mutant mice were hyperactive and exhibited a turning behavior that had them running in circles for hours on end both in cages and in open-field tests. Except for one, all mutant mice turned counterclockwise. These results indicate that Go plays a major role in motor control, motor behavior, and pain perception and predict involvement of Go in calcium channel regulation. </p><p>To analyze the function of Go-alpha in the heart, Valenzuela et al. (1997) generated knockout mice lacking both forms of Go-alpha by homologous recombination and studied the muscarinic regulation of calcium channels in cardiac muscles in Go-alpha -/- mice and controls. There was no difference in the effect of isoproterenol on the L-type voltage-dependent calcium channel (114205) in ventricular myocytes of both groups, but the inhibitory effect of carbamylcholine was almost completely abolished in the Go-alpha -/- group. This demonstrated that, in the heart, Go-alpha is specifically required for transmission of signals from the muscarinic receptor to the L-type voltage-dependent calcium channel. </p><p>Go-alpha has been implicated as the primary signaling element coupling alpha-2-adrenergic receptors to N-type calcium channels in sympathetic neurons. Jeong and Ikeda (2000) found that in rat neurons expressing a Go-alpha subunit resistant to pertussis toxin and resistant to regulators of G protein signaling proteins, norepinephrine-induced calcium current inhibition was shifted to lower concentrations. In addition to an increase in agonist potency, the expression of the resistant Go-alpha subunit retarded the current recovery after agonist removal. The data suggested that endogenous RGS proteins contribute to calcium channel modulation by regulating agonist potency and kinetics of G protein-mediated signaling in neuronal cells. </p><p>Kehrl et al. (2014) found that mutant mice heterozygous for a G184S mutation in the Gnao1 gene died in the perinatal period or early in life due to sudden death associated with severe seizures and/or increased frequency of interictal epileptiform discharges. Homozygous mutant mice were essentially nonviable. Heterozygous mice showed enhanced sensitivity to seizure kindling with a GABA antagonist compared to controls. Heterozygous knockout mice, representing a loss of function, did not show such a phenotype, suggesting that the G184S mutation results in a gain of function. Kehrl et al. (2014) noted that several studies have shown that the G184S allele results in a gain of function effect. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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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GNAO1, ILE279ASN
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<br />
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SNP: rs587777054,
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ClinVar: RCV000056405
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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 13-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo heterozygous c.836T-A transversion in the GNAO1 gene, resulting in an ile279-to-asn (I279N) substitution. The mutation specifically affected GNAO1 transcript variant 1. The mutation was found by whole-exome sequencing and was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein had some abnormal cytoplasmic localization. The patient had onset of seizures on day 4 of life. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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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GNAO1, ASP174GLY
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<br />
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SNP: rs587777055,
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ClinVar: RCV000056406, RCV002281559
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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 4-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo heterozygous c.521A-G transition in the GNAO1 gene, resulting in an asp174-to-gly (D174G) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was determined to be somatic mosaic by deep sequencing of PCR products of DNA from blood and saliva samples from the patient and her parents. The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein had some abnormal cytoplasmic localization. Electrophysiologic studies in N-type calcium channels indicated that the mutant protein had impaired current inhibition after norepinephrine application compared to wildtype, suggesting that the mutation could hamper GNAO1-mediated signaling. The patient had onset of seizures at 29 days of age. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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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GNAO1, 21-BP DEL, NT572
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<br />
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SNP: rs587777056,
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ClinVar: RCV000056407
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female infant with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo identified a de novo heterozygous 21-bp deletion (c.572_592del), resulting in an in-frame deletion of 7 residues (Thr191_Phe197). The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein accumulated in the cytoplasmic compartment instead of being normally located to the cell periphery. Electrophysiologic studies in N-type calcium channels showed that the mutant protein had increased calcium-current density compared to wildtype before norepinephrine application, and showed only a mild reduction in calcium current compared to wildtype after application of norepinephrine. The findings suggested that the mutation could hamper GNAO1-mediated signaling. The patient had onset of intractable seizures at 2 weeks of age. EEG showed a burst-suppression pattern consistent with a clinical diagnosis of Ohtahara syndrome. She died at 11 months of age. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 17</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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GNAO1, GLY203ARG
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<br />
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ClinVar: RCV000056408, RCV000255097, RCV000468248, RCV000762963, RCV001252685, RCV001256978, RCV001814039, RCV003421966
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 8-year-old girl with developmental and epileptic encephalopathy-17 (DEE17; 615473), Nakamura et al. (2013) identified a de novo heterozygous c.607G-A transition in the GNAO1 gene, resulting in a gly203-to-arg (G203R) substitution in the highly conserved switch II region that is responsible for activation of downstream effectors. The mutation was not found in the NHLBI Exome Sequencing Project database or in 408 in-house control exomes. In vitro functional expression studies in N2A cells showed that the mutant protein localized normally to the cell periphery. However, electrophysiologic studies in N-type calcium channels indicated that the similar G203T mutant protein had impaired current inhibition after norepinephrine application compared to wildtype, suggesting that the mutation could hamper GNAO1-mediated signaling. The patient showed opisthotonic posturing at 7 months of age. She later developed severe chorea. </p><p>In a 14-month-old girl with DEE17, Saitsu et al. (2016) identified a de novo heterozygous G203R mutation in the GNAO1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. The patient developed seizures on the seventh day of life. She later developed severe chorea. </p><p>Feng et al. (2017) found that the G203R variant resulted in a gain-of-function effect in a cAMP inhibition assay. The authors noted that the previously reported patients with this variant had a slightly different phenotype from classic DEE17, showing a prominent motor component. </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 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</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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GNAO1, ARG209HIS
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<br />
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SNP: rs797044878,
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ClinVar: RCV000190691, RCV000255659, RCV000490633, RCV001065368
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 brothers with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Kulkarni et al. (2016) identified a de novo heterozygous c.626G-A transition in exon 6 of the GNAO1 gene, resulting in an arg209-to-his (R209H) substitution at a conserved residue in the highly conserved switch II region, which activates downstream effectors upon GTP binding. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in either parent, suggesting germline mosaicism in one of them. The mutation was filtered against the dbSNP and 1000 Genomes Project databases and was not found in the Exome Sequencing Project database. Functional studies of the variant were not performed, but it was predicted to disrupt GNAO1 signaling. </p><p>Using exome sequencing, Menke et al. (2016) identified a de novo heterozygous R209H mutation in a 3-year-old boy with NEDIM. Functional studies of the variant were not performed. </p><p>In a 16-year-old boy with NEDIM, Ananth et al. (2016) identified a de novo heterozygous R209H mutation in the GNAO1 gene. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</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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GNAO1, ARG209CYS
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<br />
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SNP: rs886039494,
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ClinVar: RCV000256155, RCV000475848, RCV000490628, RCV000622320, RCV001003612, RCV001775107, RCV003401217
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</span>
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<span class="mim-text-font">
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<p>In an 18-year-old female with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Saitsu et al. (2016) identified a de novo heterozygous c.625C-T transition (c.625C-T, NM_020988.2) in exon 6 of the GNAO1 gene, resulting in an arg209-to-cys (R209C) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would destabilize the G-alpha-containing complexes mainly in GTP-bound active state. </p><p>Danti et al. (2017) identified a de novo heterozygous R209C mutation in 2 unrelated patients with NEDIM. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Danti et al. (2017) noted that the R209C mutation occurs in the switch II domain, which is important for regulation of downstream signaling. This residue (R209) is a mutational hotspot. </p>
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</span>
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<div>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</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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GNAO1, GLU246LYS
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<br />
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SNP: rs797044951,
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ClinVar: RCV000190803, RCV000254701, RCV000490631, RCV001580372, RCV001808530, RCV001814097, RCV001857676, RCV003996903
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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 13-year-old girl with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Saitsu et al. (2016) identified a de novo heterozygous c.736G-A transition (c.736G-A, NM_020988.2) in exon 7 of the GNAO1 gene, resulting in a glu246-to-lys (E246K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server database or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would destabilize the G-alpha-containing complexes mainly in GTP-bound active state. </p><p>In 4 patients, including 2 sibs, with NEDIM, Ananth et al. (2016) identified a de novo heterozygous E246K mutation. The mutations were found by whole-exome sequencing. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</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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GNAO1, ARG209GLY
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<br />
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SNP: rs886039494,
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ClinVar: RCV000490630
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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 4-year-old girl with neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Ananth et al. (2016) identified a de novo heterozygous c.625C-G transversion in the GNAO1 gene, resulting in an arg209-to-gly (R209G) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 NEURODEVELOPMENTAL DISORDER WITH INVOLUNTARY MOVEMENTS</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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GNAO1, GLU246GLY
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<br />
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SNP: rs1114167431,
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ClinVar: RCV000490634
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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 neurodevelopmental disorder with involuntary movements (NEDIM; 617493), Danti et al. (2017) identified a de novo heterozygous c.737A-G transition in the GNAO1 gene, resulting in a glu246-to-gly (E246G) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Ananth, A. L., Robichaux-Viehoever, A., Kim, Y.-M., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A.
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<strong>Clinical course of six children with GNAO1 mutations causing a severe and distinctive movement disorder.</strong>
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Pediat. Neurol. 59: 81-84, 2016.
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Danti, F. R., Galosi, S., Romani, M., Montomoli, M., Carss, K. J., Raymond, F. L., Parrini, E., Bianchini, C., McShane, T., Dale, R. C., Mohammad, S. S., Shah, U., and 9 others.
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<strong>GNAO1 encephalopathy: broadening the phenotype and evaluating treatment and outcome.</strong>
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Nakamura, K., Kodera, H., Akita, T., Shiina, M., Kato, M., Hoshino, H., Terashima, H., Osaka, H., Nakamura, S., Tohyama, J., Kumada, T., Furukawa, T., and 14 others.
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<strong>De novo mutations in GNAO1, encoding a G-alpha-o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.</strong>
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Ram, P. T., Horvath, C. M., Iyengar, R.
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Saitsu, H., Fukai, R., Ben-Zeev, B., Sakai, Y., Mimaki, M., Okamoto, N., Suzuki, Y., Monden, Y., Saito, H., Tziperman, B., Torio, M., Akamine, S., and 10 others.
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Strathmann, M., Wilkie, T. M., Simon, M. I.
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<strong>Alternative splicing produces transcripts encoding two forms of the alpha subunit of GTP-binding protein G(o).</strong>
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Tsukamoto, T., Toyama, R., Itoh, H., Kozasa, T., Matsuoka, M., Kaziro, Y.
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<strong>Structure of the human gene and two rat cDNAs encoding the alpha chain of GTP-binding regulatory protein G(o): two different mRNAs are generated by alternative splicing.</strong>
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Valenzuela, D., Han, X., Mende, U., Fankhauser, C., Mashimo, H., Huang, P., Pfeffer, J., Neer, E. J., Fishman, M. C.
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<strong>G-alpha-o is necessary for muscarinic regulation of Ca(2+) channels in mouse heart.</strong>
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<p class="mim-text-font">
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Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X.-N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I., Jenkins, N. A., Copeland, N. G.
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<strong>Evolution of the mammalian G protein alpha subunit multigene family.</strong>
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Nature Genet. 1: 85-91, 1992.
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[PubMed: 1302014]
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[Full Text: https://doi.org/10.1038/ng0592-85]
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Anne M. Stumpf - updated : 10/21/2020<br>Cassandra L. Kniffin - updated : 02/27/2018<br>Cassandra L. Kniffin - updated : 05/31/2017<br>Cassandra L. Kniffin - updated : 9/16/2015<br>Cassandra L. Kniffin - updated : 10/15/2013<br>Ada Hamosh - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 6/5/2006<br>Ada Hamosh - updated : 12/30/1999<br>Wilson H. Y. Lo - updated : 7/26/1999<br>Ada Hamosh - updated : 3/18/1999
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Victor A. McKusick : 10/16/1990
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