4633 lines
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Entry
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- *137192 - GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*137192</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/137192">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000166206;t=ENST00000311550" 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=2562" 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=137192" 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=ENSG00000166206;t=ENST00000311550" 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_000814,NM_001191320,NM_001191321,NM_001278631,NM_021912,NR_103801,XM_011521428" 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_000814" 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=137192" 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=08844&isoform_id=08844_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/GABRB3" 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/120773,182925,292039,292040,4503867,12548788,14714965,119578057,119578058,119578059,189067536,221040640,221044268,300797159,300797181,522838289,608785291,767983791,1039205064,2462543535,2704691120" 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/P28472" 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=2562" 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=ENSG00000166206;t=ENST00000311550" 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=GABRB3" 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=GABRB3" 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+2562" 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/GABRB3" 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:2562" 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/2562" 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=chr15&hgg_gene=ENST00000311550.10&hgg_start=26543552&hgg_end=26773763&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:4083" 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:4083" 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=137192[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=137192[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/GABRB3/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/ENSG00000166206" 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=GABRB3" 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=GABRB3" 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=GABRB3" 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=GABRB3&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/PA28497" 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:4083" 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/FBgn0010240.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:95621" 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/GABRB3#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:95621" 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/2562/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=2562" 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=WBGene00001512;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-101102-2" 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:2562" 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=GABRB3&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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137192
|
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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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GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
GABA-A RECEPTOR, BETA-3 POLYPEPTIDE
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GABRB3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GABRB3</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/15/36?start=-3&limit=10&highlight=36">15q12</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:26543552-26773763&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'})">15:26,543,552-26,773,763</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<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=612269,617113" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/36?start=-3&limit=10&highlight=36">
|
|
15q12
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Epilepsy, childhood absence, susceptibility to, 5}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612269"> 612269 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
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<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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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 43
|
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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">
|
|
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|
<a href="/entry/617113"> 617113 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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<p>Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRB3 is a member of the GABA-A receptor gene family of heteromeric pentameric ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the mammalian brain, acts. GABA-A receptors are the site of action of a number of important pharmacologic agents including barbiturates, benzodiazepines, and ethanol (summary by <a href="#30" class="mim-tip-reference" title="Whiting, P. J., Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J. S., Thompson, S. A., Wafford, K. A. <strong>Molecular and functional diversity of the expanding GABA-A receptor gene family.</strong> Ann. N.Y. Acad. Sci. 868: 645-653, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10414349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10414349</a>] [<a href="https://doi.org/10.1111/j.1749-6632.1999.tb11341.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10414349">Whiting et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10414349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>For additional general information about the GABA-A receptor gene family, see GABRA1 (<a href="/entry/137160">137160</a>).</p>
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<p><a href="#28" class="mim-tip-reference" title="Wagstaff, J., Chaillet, J. R., Lalande, M. <strong>The GABA(A) receptor beta-3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.</strong> Genomics 11: 1071-1078, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1664410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1664410</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90034-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1664410">Wagstaff et al. (1991)</a> isolated a GABA-A receptor beta-3 subunit cDNA from a human brain cDNA library. Comparison of the human beta-3 subunit amino acid sequence with beta-3 sequences from rat, cow, and chicken demonstrated a high degree of evolutionary conservation. Most of the sequence differences between species are clustered near the C terminus, within a large intracellular domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1664410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>The GABRB3 gene contains 10 exons, including 2 alternative first exons encoding signal peptides, and spans 250 kb (<a href="#7" class="mim-tip-reference" title="Glatt, K., Glatt, H., Lalande, M. <strong>Structure and organization of GABRB3 and GABRA5.</strong> Genomics 41: 63-69, 1997. Note: Erratum: Genomics 44: 155 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126483</a>] [<a href="https://doi.org/10.1006/geno.1997.4639" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126483">Glatt et al., 1997</a>; <a href="#27" class="mim-tip-reference" title="Urak, L., Feucht, M., Fathi, N., Hornik, K., Fuchs, K. <strong>A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity.</strong> Hum. Molec. Genet. 15: 2533-2541, 2006. Note: Erratum: Hum. Molec. Genet. 15: 3272 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835263</a>] [<a href="https://doi.org/10.1093/hmg/ddl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835263">Urak et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9126483+16835263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Miller, P. S., Aricescu, A. R. <strong>Crystal structure of a human GABA-A receptor.</strong> Nature 512: 270-275, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24909990[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/nature13293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24909990">Miller and Aricescu (2014)</a> described the first 3-dimensional structure of a GABA-A receptor, the human beta-3 homopentamer, at 3-angstrom resolution. This structure reveals architectural elements unique to eukaryotic cysteine-loop receptors, explains the mechanistic consequences of multiple human disease mutations, and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening an avenue for the rational design of GABA-A receptor modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24909990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Wagstaff, J., Knoll, J. H. M., Fleming, J., Kirkness, E. F., Martin-Gallardo, A., Greenberg, F., Graham, J. M., Jr., Menninger, J., Ward, D., Venter, J. C., Lalande, M. <strong>Localization of the gene encoding the GABA(A) receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15.</strong> Am. J. Hum. Genet. 49: 330-337, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714232</a>]" pmid="1714232">Wagstaff et al. (1991)</a> showed that the GABRB3 maps to the region of 15q involved in Angelman syndrome (<a href="/entry/105830">105830</a>) and Prader-Willi syndrome (<a href="/entry/176270">176270</a>). Deletion of the gene was found in patients of both types with interstitial cytogenetic deletions. The gene was also deleted in an Angelman syndrome patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. <a href="#29" class="mim-tip-reference" title="Wagstaff, J., Knoll, J. H. M., Fleming, J., Kirkness, E. F., Martin-Gallardo, A., Greenberg, F., Graham, J. M., Jr., Menninger, J., Ward, D., Venter, J. C., Lalande, M. <strong>Localization of the gene encoding the GABA(A) receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15.</strong> Am. J. Hum. Genet. 49: 330-337, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1714232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1714232</a>]" pmid="1714232">Wagstaff et al. (1991)</a> suggested that this receptor gene may be involved in the pathogenesis of one or both of these syndromes. This is the first gene to be mapped to this region. <a href="#28" class="mim-tip-reference" title="Wagstaff, J., Chaillet, J. R., Lalande, M. <strong>The GABA(A) receptor beta-3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.</strong> Genomics 11: 1071-1078, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1664410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1664410</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90034-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1664410">Wagstaff et al. (1991)</a> showed that the gene is located on mouse chromosome 7, very closely linked to 2 other genes that in the human have been mapped to the 15q11-q13 region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1714232+1664410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the combined techniques of field-inversion gel electrophoresis (FIGE) and phage genomic library screening, <a href="#23" class="mim-tip-reference" title="Sinnett, D., Wagstaff, J., Glatt, K., Woolf, E., Kirkness, E. J., Lalande, M. <strong>High-resolution mapping of the gamma-aminobutyric acid receptor subunit beta-3 and alpha-5 gene cluster on chromosome 15q11-q13, and localization of breakpoints in two Angelman syndrome patients.</strong> Am. J. Hum. Genet. 52: 1216-1229, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8389098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8389098</a>]" pmid="8389098">Sinnett et al. (1993)</a> constructed a high-resolution physical map covering nearly 1.0 Mb in the proximal region of 15q. The map showed that GABRB3 and GABRA5 (gamma-aminobutyric acid receptor alpha-5 subunit gene; <a href="/entry/137142">137142</a>) are separated by less than 100 kb and are arranged in a head-to-head configuration. GABRB3 encompasses approximately 250 kb, while GABRA5 is contained within 70 kb. The difference in size is due largely to an intron of 150 kb within GABRB3. Chromosomal rearrangement breakpoints in 2 patients with Angelman syndrome were located within the large GABRB3 intron. <a href="#19" class="mim-tip-reference" title="Russek, S. J., Farb, D. H. <strong>Mapping of the beta-2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABA-A receptor isoform.</strong> Genomics 23: 528-533, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7851879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7851879</a>] [<a href="https://doi.org/10.1006/geno.1994.1539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7851879">Russek and Farb (1994)</a> stated that the gene encoding the gamma-3 form of the GABA-A receptor (GABRG3; <a href="/entry/600233">600233</a>) is located on 15q11-q13 in a cluster with GABRA5 and GABRB3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8389098+7851879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#9" class="mim-tip-reference" title="Holopainen, I. E., Metsahonkala, E.-L., Kokkonen, H., Parkkola, R. K., Manner, T. E., Nagren, K., Korpi, E. R. <strong>Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA-A receptor beta-3 subunit deletions.</strong> Ann. Neurol. 49: 110-113, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11198279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11198279</a>] [<a href="https://doi.org/10.1002/1531-8249(200101)49:1<110::aid-ana17>3.0.co;2-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11198279">Holopainen et al. (2001)</a> used positron emission tomography (PET) to study brain binding of (11C)flumazenil in 4 patients with Angelman syndrome. Patients 1, 2, and 3 had a maternal deletion of 15q11-q13 leading to a loss of the GABRB3 gene, whereas patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) and the GABRB3 gene was spared. (11C)Flumazenil binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in patients 1 to 3 than in patient 4. <a href="#9" class="mim-tip-reference" title="Holopainen, I. E., Metsahonkala, E.-L., Kokkonen, H., Parkkola, R. K., Manner, T. E., Nagren, K., Korpi, E. R. <strong>Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA-A receptor beta-3 subunit deletions.</strong> Ann. Neurol. 49: 110-113, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11198279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11198279</a>] [<a href="https://doi.org/10.1002/1531-8249(200101)49:1<110::aid-ana17>3.0.co;2-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11198279">Holopainen et al. (2001)</a> proposed that the deletion leads to a reduced number of GABRB3 receptors, which could partially explain the neurologic deficits of Angelman syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11198279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Zinc ions regulate GABA-A receptors by inhibiting receptor function via an allosteric mechanism that is critically dependent on the receptor subunit composition. <a href="#11" class="mim-tip-reference" title="Hosie, A. M., Dunne, E. L., Harvey, R. J., Smart, T. G. <strong>Zinc-mediated inhibition of GABA-A receptors: discrete binding sites underlie subtype specificity.</strong> Nature Neurosci. 6: 362-369, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12640458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12640458</a>] [<a href="https://doi.org/10.1038/nn1030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12640458">Hosie et al. (2003)</a> used molecular modeling to identify 3 discrete sites that mediate zinc inhibition: one is located within the ion channel and comprises subunit beta-3 his267 and glu270, and the other 2 are on the external N-terminal face of the receptor and require the coordination of subunit alpha-1 (<a href="/entry/137160">137160</a>) glu137 and his141 and beta-3 glu 182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 subunit (<a href="/entry/137164">137164</a>) results from disruption of 2 of the 3 sites after subunit assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12640458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Epigenetics</em></strong></p><p>
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Using coding SNPs within the GABA receptor gene cluster on chromosome 15q11-q13, <a href="#8" class="mim-tip-reference" title="Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., Lasalle, J. M. <strong>15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders.</strong> Hum. Molec. Genet. 16: 691-703, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17339270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17339270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17339270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddm014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17339270">Hogart et al. (2007)</a> demonstrated that the GABRG3, GABRB3, and GABRA5 genes are biallelically expressed in the cerebral cortex of 21 postmortem human brain samples, and thus not normally subject to imprinting. Previously, <a href="#17" class="mim-tip-reference" title="Nicholls, R. D., Gottlieb, W., Russell, L. B., Davda, M., Horsthemke, B., Rinchik, E. M. <strong>Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11-q13 syndromes by fine-structure homology mapping in the mouse.</strong> Proc. Nat. Acad. Sci. 90: 2050-2054, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8095339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8095339</a>] [<a href="https://doi.org/10.1073/pnas.90.5.2050" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8095339">Nicholls et al. (1993)</a> showed that the mouse Gabrb3 transcript was expressed equally well from the maternal or paternal mouse chromosome 7, and they concluded that its expression was not imprinted in mouse brain. However, there was conflicting evidence on the imprinting status of human GABA-A receptor genes from <a href="#15" class="mim-tip-reference" title="Meguro, M., Mitsuya, K., Sui, H., Shigenami, K., Kugoh, H., Nakao, M., Oshimura, M. <strong>Evidence for uniparental, paternal expression of the human GABA-A receptor subunit genes, using microcell-mediated chromosome transfer.</strong> Hum. Molec. Genet. 6: 2127-2133, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9328477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9328477</a>] [<a href="https://doi.org/10.1093/hmg/6.12.2127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9328477">Meguro et al. (1997)</a>, who had found exclusive paternal expression in mouse A9 hybrids containing a single normal human chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8095339+9328477+17339270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., Lasalle, J. M. <strong>15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders.</strong> Hum. Molec. Genet. 16: 691-703, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17339270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17339270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17339270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddm014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17339270">Hogart et al. (2007)</a> found that 4 of 8 postmortem brain samples from patients with autism and 1 of 5 postmortem brain samples from patients with Rett syndrome (<a href="/entry/312750">312750</a>) had monoallelic or highly skewed allelic expression of 1 or more of the GABRB3, GABRA5, or GABRG3 genes, which correlated with decreased expression of GABRB3. These findings suggested that epigenetic dysregulation of these genes is common to both disorders. Chromatin immunoprecipitation assays in human neuroblastoma cells and normal human brain showed that MECP2 (<a href="/entry/300005">300005</a>) bound to methylated CpG sites at an intronic site within GABRB3, but there was no difference in methylation between autism samples and controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17339270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Knoll, J. H. M., Cheng, S.-D., Lalande, M. <strong>Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region.</strong> Nature Genet. 6: 41-46, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136833</a>] [<a href="https://doi.org/10.1038/ng0194-41" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136833">Knoll et al. (1994)</a> studied DNA replication within chromosome 15q11-q13, a region subject to genomic imprinting, by fluorescence in situ hybridization. Asynchronous replication between homologs was observed in cells from normal persons and in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele-specific replication timing between homologous loci were observed: paternal early/maternal late at the GABRB3 gene; maternal early/paternal late at the more distal GABRA5 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8136833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Susceptibility to Childhood Absence Epilepsy 5</em></strong></p><p>
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Childhood absence epilepsy (ECA) shows a complex nonmendelian pattern of inheritance. <a href="#27" class="mim-tip-reference" title="Urak, L., Feucht, M., Fathi, N., Hornik, K., Fuchs, K. <strong>A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity.</strong> Hum. Molec. Genet. 15: 2533-2541, 2006. Note: Erratum: Hum. Molec. Genet. 15: 3272 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835263</a>] [<a href="https://doi.org/10.1093/hmg/ddl174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835263">Urak et al. (2006)</a> screened 45 ECA patients for sequence variations in GABRB3. The authors defined 4 haplotypes between the promoter region and intron 3. A transmission disequilibrium test demonstrated significant association of this region and ECA (p = 0.007). The locus was termed ECA5 (<a href="/entry/612269">612269</a>). Reporter gene assays indicated that the disease-associated haplotype 2 promoter caused significantly lower transcriptional activity than the haplotype 1 promoter, which was overrepresented in the controls. In silico analysis suggested that an exchange from T to C within haplotype 2 may impair binding of the neuron-specific transcriptional activator N-Oct-3 (POU5F1; <a href="/entry/164177">164177</a>). Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduced the binding of N-Oct-3. The authors proposed that reduced expression of GABRB3 could be one potential cause for the development of ECA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. <strong>Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.</strong> Am. J. Hum. Genet. 82: 1249-1261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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.2008.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18514161">Tanaka et al. (2008)</a> identified 3 different heterozygous GABRB3 mutations (<a href="#0002">137192.0002</a>-<a href="#0004">137192.0004</a>) in affected members of 4 (8%) of 48 families with childhood absence epilepsy. Some patients had generalized tonic-clonic seizures; absences and accompanying seizures disappeared after 12 years of age in all four probands. Several mutation carriers were unaffected, indicating incomplete penetrance. The authors noted that patients with Angelman syndrome and deletion of GABRB3 also show absence seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18514161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Developmental and Epileptic Encephalopathy 43</em></strong></p><p>
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In 4 unrelated patients with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), the <a href="#5" class="mim-tip-reference" title="Epi4K Consortium and Epilepsy Phenome/Genome Project. <strong>De novo mutations in epileptic encephalopathies.</strong> Nature 501: 217-221, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23934111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23934111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23934111[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/nature12439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23934111">Epi4K Consortium and Epilepsy Phenome/Genome Project (2013)</a> identified different de novo heterozygous mutations in the GABRB3 gene. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 4.1 x 10(-10). Functional studies of the mutations were not performed. The <a href="#5" class="mim-tip-reference" title="Epi4K Consortium and Epilepsy Phenome/Genome Project. <strong>De novo mutations in epileptic encephalopathies.</strong> Nature 501: 217-221, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23934111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23934111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23934111[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/nature12439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23934111">Epi4K Consortium and Epilepsy Phenome/Genome Project (2013)</a> concluded that their results implicated the GABRB3 gene in epileptic encephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23934111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 7 previously unreported patients with DEE43, the <a href="#6" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified heterozygous mutations in the GABRB3 gene (see, e.g., <a href="#0005">137192.0005</a>-<a href="#0008">137192.0008</a>). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. Five of the mutations were confirmed de novo, 1 could not be confirmed de novo, and 1 segregated with a GEFS+ phenotype in a family (proband EG0258). GABRB3 mutations accounted for 1.3% of the cohort. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Janve, V. S., Hernandez, C. C., Verdier, K. M., Hu, N., Macdonald, R. L. <strong>Epileptic encephalopathy de novo GABRB mutations impair gamma-aminobutyric acid type A receptor function.</strong> Ann. Neurol. 79: 806-825, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26950270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26950270</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26950270[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26950270">Janve et al. (2016)</a> noted that 4 de novo heterozygous missense mutations in the GABRB3 gene (D120N, <a href="#0005">137192.0005</a>; E180G; Y302C; and N110D) identified in patients with DEE43 by the <a href="#5" class="mim-tip-reference" title="Epi4K Consortium and Epilepsy Phenome/Genome Project. <strong>De novo mutations in epileptic encephalopathies.</strong> Nature 501: 217-221, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23934111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23934111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23934111[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/nature12439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23934111">Epi4K Consortium and Epilepsy Phenome/Genome Project (2013)</a> occurred at highly conserved residues that are part of major structural domains. In vitro functional studies in HEK293 cells showed that the mutations either reduced GABA-evoked peak current amplitudes or altered the kinetic properties of the channel, resulting in the net loss of GABAergic inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26950270+23934111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 male patient with DEE43, <a href="#18" class="mim-tip-reference" title="Papandreou, A., McTague, A., Trump, N., Ambegaonkar, G., Ngoh, A., Meyer, E., Scott, R. H., Kurian, M. A. <strong>GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy.</strong> Dev. Med. Child Neurol. 58: 416-420, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26645412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26645412</a>] [<a href="https://doi.org/10.1111/dmcn.12976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26645412">Papandreou et al. (2016)</a> identified a de novo heterozygous missense mutation in the GABRB3 gene (T287I; <a href="#0009">137192.0009</a>). The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26645412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mother and child (cases 1 and 2) with DEE43, <a href="#1" class="mim-tip-reference" title="Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others. <strong>Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.</strong> Brain Commun. 2: fcaa162, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33585817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33585817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33585817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/braincomms/fcaa162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33585817">Absalom et al. (2020)</a> identified a heterozygous nonsense mutation in the GABRB3 gene (R194X; <a href="#0010">137192.0010</a>). The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. <a href="#1" class="mim-tip-reference" title="Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others. <strong>Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.</strong> Brain Commun. 2: fcaa162, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33585817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33585817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33585817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/braincomms/fcaa162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33585817">Absalom et al. (2020)</a> evaluated the molecular effects of de novo heterozygous mutations (E77K; T287I, <a href="#0009">137192.0009</a>) in the GABRB3 gene that were identified in 2 patients with DEE43 and hypersensitivity to vigabatrin. The functional effects of each of the mutations in GABRB3 was tested in Xenopus oocytes injected with constructs containing all 5 GABA-A receptor subunits. Each of these mutations resulted in gain of function of the GABA-A receptor, with increased sensitivity to GABA. This was thought to be due to abnormally increased chloride flux at lower GABA concentrations, which exacerbated GABAergic tonic currents. These effects on the GABA-A receptor were in contrast to those resulting from the R194X nonsense mutation in GABRB3 in their vigabatrin-responsive child with DEE43, which was predicted via modeling to result in reduced chloride flux at all GABA concentrations. <a href="#1" class="mim-tip-reference" title="Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others. <strong>Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.</strong> Brain Commun. 2: fcaa162, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33585817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33585817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33585817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/braincomms/fcaa162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33585817">Absalom et al. (2020)</a> concluded that hypersensitivity to vigabatrin therapy in patients with DEE43 results from specific mutations in GABRB3 that increase GABAergic tonic currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33585817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Insomnia</p><p><a href="#2" class="mim-tip-reference" title="Buhr, A., Bianchi, M. T., Baur, R., Courtet, P., Pignay, V., Boulenger, J. P., Gallati, S., Hinkle, D. J., Macdonald, R. L., Sigel, E. <strong>Functional characterization of the new human GABA(A) receptor mutation beta-3(R192H).</strong> Hum. Genet. 111: 154-160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189488</a>] [<a href="https://doi.org/10.1007/s00439-002-0766-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189488">Buhr et al. (2002)</a> screened 124 individuals for SNPs of the alpha-1 (GABRA1; <a href="/entry/137160">137160</a>), beta-3, and gamma-2 (GABRG2; <a href="/entry/137164">137164</a>) genes of the GABA(A) receptor in the regions corresponding to the ligand-binding domains on the protein level. In 1 patient with chronic insomnia, an arg192-to-his mutation (<a href="#0001">137192.0001</a>) was found in the GABRB3 gene in heterozygous state. Functional studies suggested the possibility of decreased GABAergic inhibition contributing to insomnia, from which some members of the patient's family suffered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Cleft Lip with or without Cleft Palate</p><p><a href="#22" class="mim-tip-reference" title="Scapoli, L., Martinelli, M., Pezzetti, F., Carinci, F., Bodo, M., Tognon, M., Carinci, P. <strong>Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate.</strong> Hum. Genet. 110: 15-20, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11810291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11810291</a>] [<a href="https://doi.org/10.1007/s00439-001-0639-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11810291">Scapoli et al. (2002)</a> found significant linkage disequilibrium between GABRB3 and nonsyndromic cleft lip with or without cleft palate (CL/P; <a href="/entry/119530">119530</a>). They noted that knockout of the Gabrb3 gene in mice causes clefting of the secondary palate only (<a href="#10" class="mim-tip-reference" title="Homanics, G. E., DeLorey, T. M., Firestone, L. L., Quinlan, J. J., Handforth, A., Harrison, N. L., Krasowski, M. D., Rick, C. E. M., Korpi, E. R., Makela, R., Brilliant, M. H., Hagiwara, N., Ferguson, C., Snyder, K., Olsen, R. W. <strong>Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior.</strong> Proc. Nat. Acad. Sci. 94: 4143-4148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108119[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.94.8.4143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108119">Homanics et al., 1997</a>). <a href="#24" class="mim-tip-reference" title="Tanabe, A., Taketani, S., Endo-Ichikawa, Y., Tokunaga, R., Ogawa, Y., Hiramoto, M. <strong>Analysis of the candidate genes responsible for non-syndromic cleft lip and palate in Japanese people.</strong> Clin. Sci. (Lond.) 99: 105-111, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10918043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10918043</a>]" pmid="10918043">Tanabe et al. (2000)</a> found no evidence that the GABRB3 gene is involved in clefting in Japanese cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11810291+10918043+9108119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Autism</p><p><a href="#3" class="mim-tip-reference" title="Buxbaum, J. D., Silverman, J. M., Smith, C. J., Greenberg, D. A., Kilifarski, M., Reichert, J., Cook, E. H., Jr., Fang, Y., Song, C.-Y., Vitale, R. <strong>Association between a GABRB3 polymorphism and autism.</strong> Molec. Psychiat. 7: 311-316, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11920158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11920158</a>] [<a href="https://doi.org/10.1038/sj.mp.4001011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11920158">Buxbaum et al. (2002)</a> noted that cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region have been described in individuals with autism. They performed an association analysis for a marker of GABRB3 called 155CA-2, using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). Four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) located within 150 kb of 155CA-2 were also assayed. Both the multiallelic TDT (P less than 0.002) and the TDT (P less than 0.004) demonstrated association between autistic disorder and 155CA-2 in these families. <a href="#3" class="mim-tip-reference" title="Buxbaum, J. D., Silverman, J. M., Smith, C. J., Greenberg, D. A., Kilifarski, M., Reichert, J., Cook, E. H., Jr., Fang, Y., Song, C.-Y., Vitale, R. <strong>Association between a GABRB3 polymorphism and autism.</strong> Molec. Psychiat. 7: 311-316, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11920158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11920158</a>] [<a href="https://doi.org/10.1038/sj.mp.4001011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11920158">Buxbaum et al. (2002)</a> suggested that genetic variants within the GABA receptor gene complex in 15q11-q13 may play a role in autistic disorder (see AUTS4; <a href="/entry/608636">608636</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11920158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Rett syndrome (<a href="/entry/312750">312750</a>), an X-linked dominant disorder caused by MECP2 (<a href="/entry/300005">300005</a>) mutations, and Angelman syndrome (<a href="/entry/105830">105830</a>), an imprinted disorder caused by maternal 15q11-q13 or UBE3A (<a href="/entry/601623">601623</a>) deficiency, have phenotypic and genetic overlap with autism. <a href="#21" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as in Rett, Angelman, and autism brain samples compared to control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. GABRB3 also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. <a href="#21" class="mim-tip-reference" title="Samaco, R. C., Hogart, A., LaSalle, J. M. <strong>Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.</strong> Hum. Molec. Genet. 14: 483-492, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15615769/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15615769</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15615769[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15615769">Samaco et al. (2005)</a> proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15615769" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Among 166 unrelated Japanese patients with autism and 412 controls, <a href="#26" class="mim-tip-reference" title="Tochigi, M., Kato, C., Koishi, S., Kawakubo, Y., Yamamoto, K., Matsumoto, H., Hashimoto, O., Kim, S.-Y., Watanabe, K., Kano, Y., Nanba, E., Kato, N., Sasaki, T. <strong>No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population.</strong> J. Hum. Genet. 52: 985-989, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17957331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17957331</a>] [<a href="https://doi.org/10.1007/s10038-007-0207-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17957331">Tochigi et al. (2007)</a> found evidence for association with SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3212337;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3212337</a>), located 2.4 kb telomeric to microsatellite 155CA-2 in the GABRB3 gene (p = 0.029 after Bonferroni correction). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17957331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#20" class="mim-tip-reference" title="Saitoh, S., Kubota, T., Ohta, T., Jinno, Y., Niikawa, N., Sugimoto, T., Wagstaff, J., Lalande, M. <strong>Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA(A) receptor beta(3)-subunit gene. (Letter)</strong> Lancet 339: 366-367, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346439</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91686-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1346439">Saitoh et al. (1992)</a> studied a highly informative family in which 3 sibs had Angelman syndrome and a deletion of one GABRB3 gene. The mother had the same deletion which she had inherited from her father. The finding supported the possibility that GABRB3 is the Angelman gene and indicated that the genes for AS and PWS are different since transmission of the deletion from the grandfather to the mother of the affected children did not result in PWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1346439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="DeLorey, T. M., Sahbaie, P., Hashemi, E., Homanics, G. E., Clark, J. D. <strong>Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder.</strong> Behav. Brain Res. 187: 207-220, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17983671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17983671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17983671[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.bbr.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17983671">DeLorey et al. (2008)</a> observed that Gabrb3-null mice showed significant deficits in activities related to social behavior, including sociability, social novelty, and nesting, compared to wildtype controls. Gabrb3-null mice also showed decreased exploratory behavior, increased stereotypic hyperactive circling behavior, and reductions in the frequency and duration of rearing episodes compared to controls. Brain tissue analysis showed that Gabrb3-null mice had hypoplasia of the cerebellar vermis compared to wildtype controls. <a href="#4" class="mim-tip-reference" title="DeLorey, T. M., Sahbaie, P., Hashemi, E., Homanics, G. E., Clark, J. D. <strong>Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder.</strong> Behav. Brain Res. 187: 207-220, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17983671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17983671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17983671[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.bbr.2007.09.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17983671">DeLorey et al. (2008)</a> concluded that the Gabrb3-null mouse provides a mouse model of autism spectrum disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17983671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>This variant, formerly titled INSOMNIA, has been reclassified because its association with the disorder has not been confirmed.</p><p>In a patient with insomnia who also had relatives who suffered from the condition, <a href="#2" class="mim-tip-reference" title="Buhr, A., Bianchi, M. T., Baur, R., Courtet, P., Pignay, V., Boulenger, J. P., Gallati, S., Hinkle, D. J., Macdonald, R. L., Sigel, E. <strong>Functional characterization of the new human GABA(A) receptor mutation beta-3(R192H).</strong> Hum. Genet. 111: 154-160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189488</a>] [<a href="https://doi.org/10.1007/s00439-002-0766-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189488">Buhr et al. (2002)</a> found a G-to-A transition in exon 6 of the GABRB3 gene, which resulted in an arg192-to-his (R192H) change in the mature beta-3 subunit. <a href="#2" class="mim-tip-reference" title="Buhr, A., Bianchi, M. T., Baur, R., Courtet, P., Pignay, V., Boulenger, J. P., Gallati, S., Hinkle, D. J., Macdonald, R. L., Sigel, E. <strong>Functional characterization of the new human GABA(A) receptor mutation beta-3(R192H).</strong> Hum. Genet. 111: 154-160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189488</a>] [<a href="https://doi.org/10.1007/s00439-002-0766-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189488">Buhr et al. (2002)</a> pointed out that the beta-3 subunit had been implicated in sleep processes independently, by the observation that mice lacking beta-3 lose the hypnotic response to oleamide (<a href="#14" class="mim-tip-reference" title="Laposky, A. D., Homanics, G. E., Baile, A., Mendelson, W. B. <strong>Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice.</strong> Neuroreport 12: 4143-4147, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11742254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11742254</a>] [<a href="https://doi.org/10.1097/00001756-200112210-00056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11742254">Laposky et al., 2001</a>). Segregation of the variant with the disorder in the family was not shown. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11742254+12189488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs25409 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs25409;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs25409?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs25409" 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=rs25409" 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=RCV000017575 OR RCV000203153 OR RCV000989276 OR RCV001511952 OR RCV001701568 OR RCV002313713 OR RCV003224101 OR RCV003934836" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017575, RCV000203153, RCV000989276, RCV001511952, RCV001701568, RCV002313713, RCV003224101, RCV003934836" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017575...</a>
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<p>In affected members of 2 unrelated Mexican families with childhood absence epilepsy-5 (ECA5; <a href="/entry/612269">612269</a>), <a href="#25" class="mim-tip-reference" title="Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. <strong>Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.</strong> Am. J. Hum. Genet. 82: 1249-1261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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.2008.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18514161">Tanaka et al. (2008)</a> identified a heterozygous 31C-T transition in exon 1a of the GABRB3 gene, resulting in a pro11-to-ser (P11S) substitution in the alternative signal peptide. A total of 3 unaffected family members from both families carried the mutation, indicating incomplete penetrance. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. <a href="#25" class="mim-tip-reference" title="Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. <strong>Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.</strong> Am. J. Hum. Genet. 82: 1249-1261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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.2008.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18514161">Tanaka et al. (2008)</a> did not identify the P11S mutation in 630 controls, but noted that it is listed as <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs25409;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs25409</a> in the SNP database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18514161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121913126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913126;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121913126?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913126" 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=rs121913126" 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=RCV000017576 OR RCV000414639 OR RCV001460762 OR RCV001719697 OR RCV002326679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017576, RCV000414639, RCV001460762, RCV001719697, RCV002326679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017576...</a>
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<p>In a patient from Honduras with childhood absence epilepsy-5 (ECA5; <a href="/entry/612269">612269</a>), <a href="#25" class="mim-tip-reference" title="Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. <strong>Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.</strong> Am. J. Hum. Genet. 82: 1249-1261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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.2008.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18514161">Tanaka et al. (2008)</a> identified a heterozygous 44C-T transition in exon 1a the GABRB3 gene, resulting in a ser15-to-phe (S15F) substitution in the alternative signal peptide. He had onset of absence seizures at age 7 years and a grand mal seizure at age 12. Absence seizures ceased at age 12. The mutation was also present in his unaffected mother and half-brother, indicating incomplete penetrance. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18514161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs71651682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs71651682;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs71651682?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs71651682" 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=rs71651682" 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=RCV000017577 OR RCV000735321 OR RCV001770039 OR RCV002513081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017577, RCV000735321, RCV001770039, RCV002513081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017577...</a>
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<p>In 2 affected members of a family from Honduras with ECA5 (<a href="/entry/612269">612269</a>), <a href="#25" class="mim-tip-reference" title="Tanaka, M., Olsen, R. W., Medina, M. T., Schwartz, E., Alonso, M. E., Duron, R. M., Castro-Ortega, R., Martinez-Juarez, I. E., Pascual-Castroviejo, I., Machado-Salas, J., Silva, R., Bailey, J. N., Bai, D., Ochoa, A., Jara-Prado, A., Pineda, G., Macdonald, R. L., Delgado-Escueta, A. V. <strong>Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.</strong> Am. J. Hum. Genet. 82: 1249-1261, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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.2008.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18514161">Tanaka et al. (2008)</a> identified a heterozygous 962G-A transition in exon 2 of the GABRB3 gene, resulting in a gly32-to-arg (G32R) substitution. Two additional family members with the mutation showed EEG abnormalities without absence seizures, and 1 had a febrile seizure. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18514161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs886037938 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037938;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=rs886037938" 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=rs886037938" 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=RCV000240945 OR RCV002274001 OR RCV002518557 OR RCV003322765 OR RCV004798820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240945, RCV002274001, RCV002518557, RCV003322765, RCV004798820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240945...</a>
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<p>In a 12-year-old boy (EG0254) with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), the <a href="#6" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.358G-A transition (c.358G-A, NM_000814.4) in the GABRB3 gene, resulting in an asp120-to-asn (D120N) substitution. The patient had onset of myoclonic-astatic epilepsy at 1 year of age after normal early development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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">rs886037939 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037939;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=rs886037939" 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=rs886037939" 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=RCV000240882" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240882" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240882</a>
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<p>In a girl (T22598) with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), the <a href="#6" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.545A-T transversion (c.545A-T, NM_000814.4) in the GABRB3 gene, resulting in a tyr182-to-phe (Y182F) substitution. The patient had onset of grimacing at 6 months of age and died of epileptic encephalopathy at 3 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</strong>
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GABRB3, GLN249LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037940 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037940;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=rs886037940" 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=rs886037940" 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=RCV000240922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240922</a>
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<p>In a 19-year-old woman (T25111) with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), the <a href="#6" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.745C-A transversion (c.745C-A, NM_000814.4) in the GABRB3 gene, resulting in a gln249-to-lys (Q249K) substitution. The patient had onset of tonic-clonic seizures at 12 years of age, but had delayed development since 6 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</strong>
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GABRB3, ALA305THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037941;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=rs886037941" 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=rs886037941" 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=RCV000240948" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240948" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240948</a>
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<p>In a 14-year-old boy (T25708) with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), the <a href="#6" class="mim-tip-reference" title="Epi4K Consortium. <strong>De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies.</strong> Am. J. Hum. Genet. 99: 287-298, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27476654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27476654</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27476654">Epi4K Consortium (2016)</a> identified a de novo heterozygous c.913G-A transition (c.913G-A, NM_000814.4) in the GABRB3 gene, resulting in an ala305-to-thr (A305T) substitution. The patient had onset of seizure-like episodes at 5 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27476654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</strong>
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GABRB3, THR287ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1595440448 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1595440448;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=rs1595440448" 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=rs1595440448" 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=RCV001994878 OR RCV002307810" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001994878, RCV002307810" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001994878...</a>
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<p>In a male patient with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), <a href="#18" class="mim-tip-reference" title="Papandreou, A., McTague, A., Trump, N., Ambegaonkar, G., Ngoh, A., Meyer, E., Scott, R. H., Kurian, M. A. <strong>GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy.</strong> Dev. Med. Child Neurol. 58: 416-420, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26645412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26645412</a>] [<a href="https://doi.org/10.1111/dmcn.12976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26645412">Papandreou et al. (2016)</a> identified a c.860C-T transition (c.860C-T, NM_021912.4) in the GABRB3 gene, resulting in a thr287-to-ile (T287I) substitution. The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy. Sanger sequencing in the patient and his parents confirmed that the mutation was de novo. The mutation was not present in the ExAC, 1000 Genomes Project, and Exome Variant Server databases. Clinical features in the patient included seizures and severe global developmental delay. He had severe hypotonia, sedation, and respiratory difficulties in response to antiepileptic treatment with vigabatrin, a GABA transaminase inhibitor. Vigabatrin was weaned and multiple other therapies were tried, but seizures continued. At 3 years and 2 months of age, he had microcephaly, hypotonia, and absence of speech. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26645412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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">rs1555368345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555368345;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=rs1555368345" 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=rs1555368345" 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=RCV002308487 OR RCV002310596 OR RCV002310597" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002308487, RCV002310596, RCV002310597" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002308487...</a>
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<p>In a mother and child (cases 1 and 2) with developmental and epileptic encephalopathy-43 (DEE43; <a href="/entry/617113">617113</a>), <a href="#1" class="mim-tip-reference" title="Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others. <strong>Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies.</strong> Brain Commun. 2: fcaa162, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33585817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33585817</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33585817[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/braincomms/fcaa162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33585817">Absalom et al. (2020)</a> identified a heterozygous c.580C-T transition in the GABRB3 gene, resulting in an arg194-to-ter (R194X) substitution. The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. The mutation was predicted to result in absent protein product due to loss of the transmembrane and pore regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33585817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Absalom, N. L., Liao, V. W. Y., Kothur, K., Indurthi, D. C., Bennetts, B., Troedson, C., Mohammad, S. S., Gupta, S., McGregor, I. S., Bowen, M. T., Lederer, D., Mary, S., and 9 others.
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[<a href="https://doi.org/10.1093/braincomms/fcaa162" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0766-7" target="_blank">Full Text</a>]
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<a id="Buxbaum2002" class="mim-anchor"></a>
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<div class="">
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[<a href="https://doi.org/10.1038/sj.mp.4001011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.bbr.2007.09.009" target="_blank">Full Text</a>]
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<a id="{Epi4K Consortium and Epilepsy Phenome/Genome Project}2013" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/nature12439" target="_blank">Full Text</a>]
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<a id="{Epi4K Consortium}2016" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/j.ajhg.2016.06.003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4639" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddm014" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1531-8249(200101)49:1<110::aid-ana17>3.0.co;2-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.94.8.4143" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nn1030" target="_blank">Full Text</a>]
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<a id="Janve2016" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1097/00001756-200112210-00056" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24909990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24909990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24909990[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=24909990" 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/nature13293" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.5.2050" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/dmcn.12976" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1539" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(92)91686-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi045" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-001-0639-5" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18514161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18514161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18514161[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=18514161" 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.2008.04.020" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10038-007-0207-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl174" target="_blank">Full Text</a>]
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<strong>The GABA(A) receptor beta-3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.</strong>
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[<a href="https://doi.org/10.1016/0888-7543(91)90034-c" target="_blank">Full Text</a>]
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Wagstaff, J., Knoll, J. H. M., Fleming, J., Kirkness, E. F., Martin-Gallardo, A., Greenberg, F., Graham, J. M., Jr., Menninger, J., Ward, D., Venter, J. C., Lalande, M.
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Whiting, P. J., Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J. S., Thompson, S. A., Wafford, K. A.
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[<a href="https://doi.org/10.1111/j.1749-6632.1999.tb11341.x" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/11/2022
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/11/2016<br>Cassandra L. Kniffin - updated : 09/19/2016<br>Ada Hamosh - updated : 10/17/2014<br>Cassandra L. Kniffin - updated : 7/19/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 9/10/2008<br>George E. Tiller - updated : 7/24/2008<br>Cassandra L. Kniffin - updated : 5/5/2008<br>George E. Tiller - updated : 1/3/2008<br>Cassandra L. Kniffin - updated : 3/18/2003<br>Victor A. McKusick - updated : 10/2/2002<br>John Logan Black, III - updated : 8/14/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 1/25/2002<br>Rebekah S. Rasooly - updated : 5/29/1998<br>Victor A. McKusick - updated : 11/20/1997
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Victor A. McKusick : 10/25/1991
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carol : 11/15/2022
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carol : 11/11/2022<br>carol : 10/24/2022<br>alopez : 11/19/2020<br>carol : 11/11/2020<br>alopez : 11/10/2020<br>joanna : 10/18/2020<br>carol : 10/12/2016<br>ckniffin : 10/11/2016<br>alopez : 09/20/2016<br>ckniffin : 09/19/2016<br>alopez : 10/17/2014<br>carol : 9/10/2014<br>terry : 7/6/2012<br>terry : 5/25/2012<br>wwang : 7/27/2010<br>ckniffin : 7/19/2010<br>wwang : 7/15/2010<br>ckniffin : 7/13/2010<br>carol : 12/3/2009<br>ckniffin : 10/2/2009<br>carol : 9/24/2008<br>wwang : 9/15/2008<br>ckniffin : 9/10/2008<br>alopez : 7/24/2008<br>alopez : 7/24/2008<br>wwang : 5/14/2008<br>ckniffin : 5/5/2008<br>wwang : 1/11/2008<br>terry : 1/3/2008<br>terry : 8/15/2003<br>alopez : 4/1/2003<br>carol : 3/18/2003<br>ckniffin : 3/18/2003<br>tkritzer : 10/4/2002<br>terry : 10/2/2002<br>carol : 8/14/2002<br>cwells : 7/16/2002<br>terry : 7/2/2002<br>terry : 3/11/2002<br>carol : 2/6/2002<br>carol : 2/6/2002<br>terry : 1/25/2002<br>alopez : 5/29/1998<br>terry : 11/24/1997<br>terry : 11/20/1997<br>mark : 4/10/1997<br>carol : 2/7/1994<br>carol : 6/16/1993<br>carol : 10/9/1992<br>carol : 9/8/1992<br>supermim : 3/16/1992<br>carol : 12/5/1991
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<strong>*</strong> 137192
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GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3
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GABA-A RECEPTOR, BETA-3 POLYPEPTIDE
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<strong><em>HGNC Approved Gene Symbol: GABRB3</em></strong>
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Cytogenetic location: 15q12
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:26,543,552-26,773,763 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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15q12
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{Epilepsy, childhood absence, susceptibility to, 5}
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<span class="mim-font">
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612269
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3
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Developmental and epileptic encephalopathy 43
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617113
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRB3 is a member of the GABA-A receptor gene family of heteromeric pentameric ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the mammalian brain, acts. GABA-A receptors are the site of action of a number of important pharmacologic agents including barbiturates, benzodiazepines, and ethanol (summary by Whiting et al., 1999). </p><p>For additional general information about the GABA-A receptor gene family, see GABRA1 (137160).</p>
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<strong>Cloning and Expression</strong>
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<p>Wagstaff et al. (1991) isolated a GABA-A receptor beta-3 subunit cDNA from a human brain cDNA library. Comparison of the human beta-3 subunit amino acid sequence with beta-3 sequences from rat, cow, and chicken demonstrated a high degree of evolutionary conservation. Most of the sequence differences between species are clustered near the C terminus, within a large intracellular domain of the protein. </p>
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<strong>Gene Structure</strong>
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<p>The GABRB3 gene contains 10 exons, including 2 alternative first exons encoding signal peptides, and spans 250 kb (Glatt et al., 1997; Urak et al., 2006). </p>
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<strong>Biochemical Features</strong>
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<p>Miller and Aricescu (2014) described the first 3-dimensional structure of a GABA-A receptor, the human beta-3 homopentamer, at 3-angstrom resolution. This structure reveals architectural elements unique to eukaryotic cysteine-loop receptors, explains the mechanistic consequences of multiple human disease mutations, and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening an avenue for the rational design of GABA-A receptor modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. </p>
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<strong>Mapping</strong>
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<p>Wagstaff et al. (1991) showed that the GABRB3 maps to the region of 15q involved in Angelman syndrome (105830) and Prader-Willi syndrome (176270). Deletion of the gene was found in patients of both types with interstitial cytogenetic deletions. The gene was also deleted in an Angelman syndrome patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. Wagstaff et al. (1991) suggested that this receptor gene may be involved in the pathogenesis of one or both of these syndromes. This is the first gene to be mapped to this region. Wagstaff et al. (1991) showed that the gene is located on mouse chromosome 7, very closely linked to 2 other genes that in the human have been mapped to the 15q11-q13 region. </p><p>Using the combined techniques of field-inversion gel electrophoresis (FIGE) and phage genomic library screening, Sinnett et al. (1993) constructed a high-resolution physical map covering nearly 1.0 Mb in the proximal region of 15q. The map showed that GABRB3 and GABRA5 (gamma-aminobutyric acid receptor alpha-5 subunit gene; 137142) are separated by less than 100 kb and are arranged in a head-to-head configuration. GABRB3 encompasses approximately 250 kb, while GABRA5 is contained within 70 kb. The difference in size is due largely to an intron of 150 kb within GABRB3. Chromosomal rearrangement breakpoints in 2 patients with Angelman syndrome were located within the large GABRB3 intron. Russek and Farb (1994) stated that the gene encoding the gamma-3 form of the GABA-A receptor (GABRG3; 600233) is located on 15q11-q13 in a cluster with GABRA5 and GABRB3. </p>
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<strong>Gene Function</strong>
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<p>Holopainen et al. (2001) used positron emission tomography (PET) to study brain binding of (11C)flumazenil in 4 patients with Angelman syndrome. Patients 1, 2, and 3 had a maternal deletion of 15q11-q13 leading to a loss of the GABRB3 gene, whereas patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) and the GABRB3 gene was spared. (11C)Flumazenil binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in patients 1 to 3 than in patient 4. Holopainen et al. (2001) proposed that the deletion leads to a reduced number of GABRB3 receptors, which could partially explain the neurologic deficits of Angelman syndrome patients. </p><p>Zinc ions regulate GABA-A receptors by inhibiting receptor function via an allosteric mechanism that is critically dependent on the receptor subunit composition. Hosie et al. (2003) used molecular modeling to identify 3 discrete sites that mediate zinc inhibition: one is located within the ion channel and comprises subunit beta-3 his267 and glu270, and the other 2 are on the external N-terminal face of the receptor and require the coordination of subunit alpha-1 (137160) glu137 and his141 and beta-3 glu 182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 subunit (137164) results from disruption of 2 of the 3 sites after subunit assembly. </p><p><strong><em>Epigenetics</em></strong></p><p>
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Using coding SNPs within the GABA receptor gene cluster on chromosome 15q11-q13, Hogart et al. (2007) demonstrated that the GABRG3, GABRB3, and GABRA5 genes are biallelically expressed in the cerebral cortex of 21 postmortem human brain samples, and thus not normally subject to imprinting. Previously, Nicholls et al. (1993) showed that the mouse Gabrb3 transcript was expressed equally well from the maternal or paternal mouse chromosome 7, and they concluded that its expression was not imprinted in mouse brain. However, there was conflicting evidence on the imprinting status of human GABA-A receptor genes from Meguro et al. (1997), who had found exclusive paternal expression in mouse A9 hybrids containing a single normal human chromosome 15. </p><p>Hogart et al. (2007) found that 4 of 8 postmortem brain samples from patients with autism and 1 of 5 postmortem brain samples from patients with Rett syndrome (312750) had monoallelic or highly skewed allelic expression of 1 or more of the GABRB3, GABRA5, or GABRG3 genes, which correlated with decreased expression of GABRB3. These findings suggested that epigenetic dysregulation of these genes is common to both disorders. Chromatin immunoprecipitation assays in human neuroblastoma cells and normal human brain showed that MECP2 (300005) bound to methylated CpG sites at an intronic site within GABRB3, but there was no difference in methylation between autism samples and controls. </p><p>Knoll et al. (1994) studied DNA replication within chromosome 15q11-q13, a region subject to genomic imprinting, by fluorescence in situ hybridization. Asynchronous replication between homologs was observed in cells from normal persons and in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele-specific replication timing between homologous loci were observed: paternal early/maternal late at the GABRB3 gene; maternal early/paternal late at the more distal GABRA5 locus. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Susceptibility to Childhood Absence Epilepsy 5</em></strong></p><p>
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Childhood absence epilepsy (ECA) shows a complex nonmendelian pattern of inheritance. Urak et al. (2006) screened 45 ECA patients for sequence variations in GABRB3. The authors defined 4 haplotypes between the promoter region and intron 3. A transmission disequilibrium test demonstrated significant association of this region and ECA (p = 0.007). The locus was termed ECA5 (612269). Reporter gene assays indicated that the disease-associated haplotype 2 promoter caused significantly lower transcriptional activity than the haplotype 1 promoter, which was overrepresented in the controls. In silico analysis suggested that an exchange from T to C within haplotype 2 may impair binding of the neuron-specific transcriptional activator N-Oct-3 (POU5F1; 164177). Electrophoretic mobility shift assays demonstrated that the respective polymorphism reduced the binding of N-Oct-3. The authors proposed that reduced expression of GABRB3 could be one potential cause for the development of ECA. </p><p>Tanaka et al. (2008) identified 3 different heterozygous GABRB3 mutations (137192.0002-137192.0004) in affected members of 4 (8%) of 48 families with childhood absence epilepsy. Some patients had generalized tonic-clonic seizures; absences and accompanying seizures disappeared after 12 years of age in all four probands. Several mutation carriers were unaffected, indicating incomplete penetrance. The authors noted that patients with Angelman syndrome and deletion of GABRB3 also show absence seizures. </p><p><strong><em>Developmental and Epileptic Encephalopathy 43</em></strong></p><p>
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In 4 unrelated patients with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified different de novo heterozygous mutations in the GABRB3 gene. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 4.1 x 10(-10). Functional studies of the mutations were not performed. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy. </p><p>In 7 previously unreported patients with DEE43, the Epi4K Consortium (2016) identified heterozygous mutations in the GABRB3 gene (see, e.g., 137192.0005-137192.0008). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. Five of the mutations were confirmed de novo, 1 could not be confirmed de novo, and 1 segregated with a GEFS+ phenotype in a family (proband EG0258). GABRB3 mutations accounted for 1.3% of the cohort. </p><p>Janve et al. (2016) noted that 4 de novo heterozygous missense mutations in the GABRB3 gene (D120N, 137192.0005; E180G; Y302C; and N110D) identified in patients with DEE43 by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) occurred at highly conserved residues that are part of major structural domains. In vitro functional studies in HEK293 cells showed that the mutations either reduced GABA-evoked peak current amplitudes or altered the kinetic properties of the channel, resulting in the net loss of GABAergic inhibition. </p><p>In a male patient with DEE43, Papandreou et al. (2016) identified a de novo heterozygous missense mutation in the GABRB3 gene (T287I; 137192.0009). The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy and confirmed by Sanger sequencing. </p><p>In a mother and child (cases 1 and 2) with DEE43, Absalom et al. (2020) identified a heterozygous nonsense mutation in the GABRB3 gene (R194X; 137192.0010). The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. Absalom et al. (2020) evaluated the molecular effects of de novo heterozygous mutations (E77K; T287I, 137192.0009) in the GABRB3 gene that were identified in 2 patients with DEE43 and hypersensitivity to vigabatrin. The functional effects of each of the mutations in GABRB3 was tested in Xenopus oocytes injected with constructs containing all 5 GABA-A receptor subunits. Each of these mutations resulted in gain of function of the GABA-A receptor, with increased sensitivity to GABA. This was thought to be due to abnormally increased chloride flux at lower GABA concentrations, which exacerbated GABAergic tonic currents. These effects on the GABA-A receptor were in contrast to those resulting from the R194X nonsense mutation in GABRB3 in their vigabatrin-responsive child with DEE43, which was predicted via modeling to result in reduced chloride flux at all GABA concentrations. Absalom et al. (2020) concluded that hypersensitivity to vigabatrin therapy in patients with DEE43 results from specific mutations in GABRB3 that increase GABAergic tonic currents. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Insomnia</p><p>Buhr et al. (2002) screened 124 individuals for SNPs of the alpha-1 (GABRA1; 137160), beta-3, and gamma-2 (GABRG2; 137164) genes of the GABA(A) receptor in the regions corresponding to the ligand-binding domains on the protein level. In 1 patient with chronic insomnia, an arg192-to-his mutation (137192.0001) was found in the GABRB3 gene in heterozygous state. Functional studies suggested the possibility of decreased GABAergic inhibition contributing to insomnia, from which some members of the patient's family suffered. </p><p>Cleft Lip with or without Cleft Palate</p><p>Scapoli et al. (2002) found significant linkage disequilibrium between GABRB3 and nonsyndromic cleft lip with or without cleft palate (CL/P; 119530). They noted that knockout of the Gabrb3 gene in mice causes clefting of the secondary palate only (Homanics et al., 1997). Tanabe et al. (2000) found no evidence that the GABRB3 gene is involved in clefting in Japanese cases. </p><p>Autism</p><p>Buxbaum et al. (2002) noted that cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region have been described in individuals with autism. They performed an association analysis for a marker of GABRB3 called 155CA-2, using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). Four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) located within 150 kb of 155CA-2 were also assayed. Both the multiallelic TDT (P less than 0.002) and the TDT (P less than 0.004) demonstrated association between autistic disorder and 155CA-2 in these families. Buxbaum et al. (2002) suggested that genetic variants within the GABA receptor gene complex in 15q11-q13 may play a role in autistic disorder (see AUTS4; 608636). </p><p>Rett syndrome (312750), an X-linked dominant disorder caused by MECP2 (300005) mutations, and Angelman syndrome (105830), an imprinted disorder caused by maternal 15q11-q13 or UBE3A (601623) deficiency, have phenotypic and genetic overlap with autism. Samaco et al. (2005) tested the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods revealed significant defects in UBE3A expression in 2 different Mecp2-deficient mouse strains, as well as in Rett, Angelman, and autism brain samples compared to control samples. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null mouse brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. GABRB3 also showed significantly reduced expression in multiple Rett, Angelman, and autism brain samples, as well as Mecp2-deficient mice. Samaco et al. (2005) proposed an overlapping pathway of gene dysregulation within chromosome 15q11-q13 in Rett syndrome, Angelman syndrome, and autism, and implicated MECP2 in the regulation of UBE3A and GABRB3 expression in the postnatal mammalian brain. </p><p>Among 166 unrelated Japanese patients with autism and 412 controls, Tochigi et al. (2007) found evidence for association with SNP (rs3212337), located 2.4 kb telomeric to microsatellite 155CA-2 in the GABRB3 gene (p = 0.029 after Bonferroni correction). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</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>Saitoh et al. (1992) studied a highly informative family in which 3 sibs had Angelman syndrome and a deletion of one GABRB3 gene. The mother had the same deletion which she had inherited from her father. The finding supported the possibility that GABRB3 is the Angelman gene and indicated that the genes for AS and PWS are different since transmission of the deletion from the grandfather to the mother of the affected children did not result in PWS. </p>
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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>DeLorey et al. (2008) observed that Gabrb3-null mice showed significant deficits in activities related to social behavior, including sociability, social novelty, and nesting, compared to wildtype controls. Gabrb3-null mice also showed decreased exploratory behavior, increased stereotypic hyperactive circling behavior, and reductions in the frequency and duration of rearing episodes compared to controls. Brain tissue analysis showed that Gabrb3-null mice had hypoplasia of the cerebellar vermis compared to wildtype controls. DeLorey et al. (2008) concluded that the Gabrb3-null mouse provides a mouse model of autism spectrum disorder. </p>
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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>10 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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</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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GABRB3, ARG192HIS
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<br />
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SNP: rs121913125,
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gnomAD: rs121913125,
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ClinVar: RCV000017574, RCV000703382, RCV001787803, RCV003133118
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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>This variant, formerly titled INSOMNIA, has been reclassified because its association with the disorder has not been confirmed.</p><p>In a patient with insomnia who also had relatives who suffered from the condition, Buhr et al. (2002) found a G-to-A transition in exon 6 of the GABRB3 gene, which resulted in an arg192-to-his (R192H) change in the mature beta-3 subunit. Buhr et al. (2002) pointed out that the beta-3 subunit had been implicated in sleep processes independently, by the observation that mice lacking beta-3 lose the hypnotic response to oleamide (Laposky et al., 2001). Segregation of the variant with the disorder in the family was not shown. </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 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5</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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GABRB3, PRO11SER
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<br />
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SNP: rs25409,
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gnomAD: rs25409,
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ClinVar: RCV000017575, RCV000203153, RCV000989276, RCV001511952, RCV001701568, RCV002313713, RCV003224101, RCV003934836
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 unrelated Mexican families with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 31C-T transition in exon 1a of the GABRB3 gene, resulting in a pro11-to-ser (P11S) substitution in the alternative signal peptide. A total of 3 unaffected family members from both families carried the mutation, indicating incomplete penetrance. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. Tanaka et al. (2008) did not identify the P11S mutation in 630 controls, but noted that it is listed as rs25409 in the SNP database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5</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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GABRB3, SER15PHE
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<br />
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SNP: rs121913126,
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gnomAD: rs121913126,
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ClinVar: RCV000017576, RCV000414639, RCV001460762, RCV001719697, RCV002326679
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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 from Honduras with childhood absence epilepsy-5 (ECA5; 612269), Tanaka et al. (2008) identified a heterozygous 44C-T transition in exon 1a the GABRB3 gene, resulting in a ser15-to-phe (S15F) substitution in the alternative signal peptide. He had onset of absence seizures at age 7 years and a grand mal seizure at age 12. Absence seizures ceased at age 12. The mutation was also present in his unaffected mother and half-brother, indicating incomplete penetrance. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. </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 EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 5</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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GABRB3, GLY32ARG
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<br />
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SNP: rs71651682,
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gnomAD: rs71651682,
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ClinVar: RCV000017577, RCV000735321, RCV001770039, RCV002513081
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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 affected members of a family from Honduras with ECA5 (612269), Tanaka et al. (2008) identified a heterozygous 962G-A transition in exon 2 of the GABRB3 gene, resulting in a gly32-to-arg (G32R) substitution. Two additional family members with the mutation showed EEG abnormalities without absence seizures, and 1 had a febrile seizure. The mutation was not identified in 630 controls. In vitro cellular functional expression studies showed that the mutant protein was hyperglycosylated and had reduced mean current densities compared to wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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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GABRB3, ASP120ASN
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<br />
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|
|
SNP: rs886037938,
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|
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ClinVar: RCV000240945, RCV002274001, RCV002518557, RCV003322765, RCV004798820
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|
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a 12-year-old boy (EG0254) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.358G-A transition (c.358G-A, NM_000814.4) in the GABRB3 gene, resulting in an asp120-to-asn (D120N) substitution. The patient had onset of myoclonic-astatic epilepsy at 1 year of age after normal early development. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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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GABRB3, TYR182PHE
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<br />
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|
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SNP: rs886037939,
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ClinVar: RCV000240882
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a girl (T22598) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.545A-T transversion (c.545A-T, NM_000814.4) in the GABRB3 gene, resulting in a tyr182-to-phe (Y182F) substitution. The patient had onset of grimacing at 6 months of age and died of epileptic encephalopathy at 3 years 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>
|
|
<span class="mim-font">
|
|
<strong>.0007 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
GABRB3, GLN249LYS
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<br />
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|
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SNP: rs886037940,
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ClinVar: RCV000240922
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 19-year-old woman (T25111) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.745C-A transversion (c.745C-A, NM_000814.4) in the GABRB3 gene, resulting in a gln249-to-lys (Q249K) substitution. The patient had onset of tonic-clonic seizures at 12 years of age, but had delayed development since 6 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">
|
|
<strong>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GABRB3, ALA305THR
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<br />
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SNP: rs886037941,
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ClinVar: RCV000240948
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 14-year-old boy (T25708) with developmental and epileptic encephalopathy-43 (DEE43; 617113), the Epi4K Consortium (2016) identified a de novo heterozygous c.913G-A transition (c.913G-A, NM_000814.4) in the GABRB3 gene, resulting in an ala305-to-thr (A305T) substitution. The patient had onset of seizure-like episodes at 5 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>.0009 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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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GABRB3, THR287ILE
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<br />
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SNP: rs1595440448,
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ClinVar: RCV001994878, RCV002307810
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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 male patient with developmental and epileptic encephalopathy-43 (DEE43; 617113), Papandreou et al. (2016) identified a c.860C-T transition (c.860C-T, NM_021912.4) in the GABRB3 gene, resulting in a thr287-to-ile (T287I) substitution. The mutation was identified by sequencing of a panel of 48 genes associated with early infantile epileptic encephalopathy. Sanger sequencing in the patient and his parents confirmed that the mutation was de novo. The mutation was not present in the ExAC, 1000 Genomes Project, and Exome Variant Server databases. Clinical features in the patient included seizures and severe global developmental delay. He had severe hypotonia, sedation, and respiratory difficulties in response to antiepileptic treatment with vigabatrin, a GABA transaminase inhibitor. Vigabatrin was weaned and multiple other therapies were tried, but seizures continued. At 3 years and 2 months of age, he had microcephaly, hypotonia, and absence of speech. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 43</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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GABRB3, ARG194TER
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<br />
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SNP: rs1555368345,
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ClinVar: RCV002308487, RCV002310596, RCV002310597
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a mother and child (cases 1 and 2) with developmental and epileptic encephalopathy-43 (DEE43; 617113), Absalom et al. (2020) identified a heterozygous c.580C-T transition in the GABRB3 gene, resulting in an arg194-to-ter (R194X) substitution. The mutation was identified by sequencing of a panel of genes associated with epilepsy and confirmed by Sanger sequencing. The mutation was predicted to result in absent protein product due to loss of the transmembrane and pore regions. </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="text-nowrap mim-text-font">
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Contributors:
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</span>
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Hilary J. Vernon - updated : 11/11/2022<br>Cassandra L. Kniffin - updated : 10/11/2016<br>Cassandra L. Kniffin - updated : 09/19/2016<br>Ada Hamosh - updated : 10/17/2014<br>Cassandra L. Kniffin - updated : 7/19/2010<br>Cassandra L. Kniffin - updated : 7/13/2010<br>Cassandra L. Kniffin - updated : 9/10/2008<br>George E. Tiller - updated : 7/24/2008<br>Cassandra L. Kniffin - updated : 5/5/2008<br>George E. Tiller - updated : 1/3/2008<br>Cassandra L. Kniffin - updated : 3/18/2003<br>Victor A. McKusick - updated : 10/2/2002<br>John Logan Black, III - updated : 8/14/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 1/25/2002<br>Rebekah S. Rasooly - updated : 5/29/1998<br>Victor A. McKusick - updated : 11/20/1997
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Victor A. McKusick : 10/25/1991
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