4360 lines
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Entry
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- *604447 - GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-5; GNB5
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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">*604447</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604447">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<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 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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<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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</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=ENSG00000069966;t=ENST00000261837" 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=10681" 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=604447" 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 class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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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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<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=ENSG00000069966;t=ENST00000261837" 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_001379343,NM_006578,NM_016194,XM_011521162" 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_016194" 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=604447" 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 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=09191&isoform_id=09191_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/GNB5" 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/2570404,5729852,5911941,10505352,15079705,15559278,20257504,20336270,38258891,119597842,119597843,119597844,119597845,119597846,119597847,119597848,119597849,119597850,158261683,189054539,193785083,767983133,1827280164,2104758977,2462542596" 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/O14775" 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=10681" 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=ENSG00000069966;t=ENST00000261837" 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=GNB5" 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=GNB5" 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+10681" 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/GNB5" 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:10681" 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/10681" 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=ENST00000261837.12&hgg_start=52115100&hgg_end=52191392&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604447[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=604447[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/GNB5/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/ENSG00000069966" 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=GNB5" 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=GNB5" 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=GNB5" 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=GNB5&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/PA28780" 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:4401" 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/FBgn0030011.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:101848" 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/GNB5#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:101848" 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/10681/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=10681" 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=WBGene00001680;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-1712" 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">
|
|
<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:10681" 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=GNB5&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1186711002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604447
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-5; GNB5
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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>
|
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<span class="mim-font">
|
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GB5
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GNB5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GNB5</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>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/15/221?start=-3&limit=10&highlight=221">15q21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:52115100-52191392&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'})">15:52,115,100-52,191,392</a> </span>
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
|
|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617173,617182" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/221?start=-3&limit=10&highlight=221">
|
|
15q21.2
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<a href="/entry/617173"> 617173 </a>
|
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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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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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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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<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">
|
|
Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/617182"> 617182 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</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="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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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
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<p>The GNB5 gene encodes a beta subunit of heterotrimeric GTP-binding proteins (G proteins). GNB5 forms complexes with members of the R7 regulator family of RGS proteins (see, e.g., RGS7, <a href="/entry/602517">602517</a> and RGS9, <a href="/entry/604067">604067</a>) as well as with R7-binding protein (RGS7BP; <a href="/entry/610890">610890</a>), and is essential for the structural integrity and proteolytic stability of R7 RGS complexes, which serve as negative regulators of G protein-coupled receptor (GPCR) signaling. GNB5 is expressed in the brain and plays a role in neurotransmitter signaling, including via the dopamine D2 receptor (DRD2; <a href="/entry/126450">126450</a>) (summary by <a href="#17" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al., 2012</a> and <a href="#10" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al., 2016</a>). GNB5 also interacts with G protein-coupled inward rectifier potassium channels (GIRK; see, e.g., GIRK2, <a href="/entry/600877">600877</a>) involved in the hyperpolarization of cell membranes (summary by <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21766168+27523599+27677260" 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 structural information about G proteins, see <a href="/entry/600874">600874</a>.</p>
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<p>Using a degenerate PCR approach to screen a human brain cDNA library, <a href="#4" class="mim-tip-reference" title="Jones, P. G., Lombardi, S. J., Cockett, M. I. <strong>Cloning and tissue distribution of the human G protein beta-5 cDNA.</strong> Biochim. Biophys. Acta 1402: 288-291, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9606987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9606987</a>] [<a href="https://doi.org/10.1016/s0167-4889(98)00017-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9606987">Jones et al. (1998)</a> cloned the beta-5 subunit, symbolized GNB5, of G protein. In contrast to beta subunits 1 through 4, which are at least 83% homologous, GNB5 is only 50% homologous to the other beta subunits. On the other hand, the predicted 353-amino acid protein sequence is 99.4% homologous to the mouse beta-5 protein, with only 2 conservative amino acid differences. Northern blot analysis revealed that mouse Gnb5 is expressed predominantly in brain (<a href="#16" class="mim-tip-reference" title="Watson, A. J., Katz, A., Simon, M. I. <strong>A fifth member of the mammalian G-protein beta subunit family: expression in brain and activation of the beta-2 isotype of phospholipase C.</strong> J. Biol. Chem. 269: 22150-22156, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8071339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8071339</a>]" pmid="8071339">Watson et al., 1994</a>), whereas human GNB5 is expressed at high levels not only in brain but also in pancreas, kidney, and heart (<a href="#4" class="mim-tip-reference" title="Jones, P. G., Lombardi, S. J., Cockett, M. I. <strong>Cloning and tissue distribution of the human G protein beta-5 cDNA.</strong> Biochim. Biophys. Acta 1402: 288-291, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9606987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9606987</a>] [<a href="https://doi.org/10.1016/s0167-4889(98)00017-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9606987">Jones et al., 1998</a>), as a major 3.0- and minor 2.0- and 9.0-kb transcripts. Within the brain, <a href="#4" class="mim-tip-reference" title="Jones, P. G., Lombardi, S. J., Cockett, M. I. <strong>Cloning and tissue distribution of the human G protein beta-5 cDNA.</strong> Biochim. Biophys. Acta 1402: 288-291, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9606987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9606987</a>] [<a href="https://doi.org/10.1016/s0167-4889(98)00017-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9606987">Jones et al. (1998)</a> detected highest expression in cerebellum, cerebral cortex, occipital pole, frontal lobe, temporal lobe, and caudate putamen, and lowest expression in corpus callosum and spinal cord. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8071339+9606987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Watson, A. J., Aragay, A. M., Slepak, V. Z., Simon, M. I. <strong>A novel form of the G protein beta subunit G-beta-5 is specifically expressed in the vertebrate retina.</strong> J. Biol. Chem. 271: 28154-28160, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910430</a>] [<a href="https://doi.org/10.1074/jbc.271.45.28154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8910430">Watson et al. (1996)</a> reported the cloning of a retina-specific cDNA, termed G-beta-5L, in the mouse, which is identical to GNB5 except for an additional 126-bp 5-prime exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8910430" 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="Rosskopf, D., Nikula, C., Manthey, I., Joisten, M., Frey, U., Kohnen, S., Siffert, W. <strong>The human G protein beta-4 subunit: gene structure, expression, G-gamma and effector interaction.</strong> FEBS Lett. 544: 27-32, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12782285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12782285</a>] [<a href="https://doi.org/10.1016/s0014-5793(03)00441-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12782285">Rosskopf et al. (2003)</a> determined that the GNB5 gene contains 12 exons. The first exon is noncoding and exons 2 and 3 contain alternate ATG translational start codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12782285" 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="#2" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 7/16/2018."None>Gross (2018)</a> mapped the GNB5 gene to chromosome 15q21.2 based on an alignment of the GNB5 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC013997" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC013997</a>) with the genomic sequence (GRCh38).</p>
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<p>GNB5 interacts with regulator of G protein signaling (RGS) proteins containing the G protein gamma-like (GGL) domain: RGS6 (<a href="/entry/603894">603894</a>), RGS7 (<a href="/entry/602517">602517</a>), RGS9 (<a href="/entry/604067">604067</a>), and RGS11 (<a href="/entry/603895">603895</a>). <a href="#1" class="mim-tip-reference" title="Chen, C.-K., Eversole-Cire, P., Zhang, H., Mancino, V., Chen, Y.-J., He, W., Wensel, T. G., Simon, M. I. <strong>Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit G-beta-5.</strong> Proc. Nat. Acad. Sci. 100: 6604-6609, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12738888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12738888</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12738888[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.0631825100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12738888">Chen et al. (2003)</a> presented data indicating that GNB5 and GGL domain-containing RGS proteins are obligate partners and supporting the notion that GNB5 functions as a component of the GTPase-accelerating protein (GAP) complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12738888" 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 mouse hippocampus and striatum, <a href="#17" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al. (2012)</a> found expression of Gnb5 in pre- and postsynaptic regions and in dendritic shafts and spines of neurons. Localization was observed both at the plasma membrane and in intracellular regions, as well as at the active zone of the axonal terminals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21766168" 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>Lodder-Merla Syndrome Type 1 with Impaired Intellectual Development and Cardiac Arrhythmia</em></strong></p><p>
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In 6 patients from 4 unrelated families with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified homozygous or compound heterozygous truncating mutations in the GNB5 gene (<a href="#0001">604447.0001</a>-<a href="#0005">604447.0005</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants were not performed; studies of patient cells, performed only in 1 family (family A) with compound heterozygous truncating variants, demonstrated that both alleles were subject to nonsense-mediated mRNA, resulting in a putative complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 consanguineous Turkish family in which 5 sibs and their second cousin had LDMLS1, <a href="#13" class="mim-tip-reference" title="Turkdogan, D., Usluer, S., Akalin, F., Agyuz, U., Aslan, E. S. <strong>Familial early infantile epileptic encephalopathy and cardiac conduction disorder: A rare cause of SUDEP in infancy.</strong> Seizure 50: 171-172, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28697420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28697420</a>] [<a href="https://doi.org/10.1016/j.seizure.2017.06.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28697420">Turkdogan et al. (2017)</a> identified homozygosity for a 1-bp deletion in the GNB5 gene (<a href="#0007">604447.0007</a>) that segregated with disease in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28697420" 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 2-year-old boy with severe developmental delay and bradycardia, <a href="#14" class="mim-tip-reference" title="Vernon, H., Cohen, J., De Nittis, P., Fatemi, A., McClellan, R., Goldstein, A., Malerba, N., Guex, N., Reymond, A., Merla, G. <strong>Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.</strong> Clin. Genet. 93: 1254-1256, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29368331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29368331</a>] [<a href="https://doi.org/10.1111/cge.13194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29368331">Vernon et al. (2018)</a> identified compound heterozygosity for a 5-bp deletion (<a href="#0008">604447.0008</a>) and a missense mutation (R246Q; <a href="#0009">604447.0009</a>) in the GNB5 gene. The mutations segregated with disease in the family and were not found in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29368331" 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 3-year-old girl of South Asian descent with global developmental delay, seizures, severe bradycardia, and retinopathy, <a href="#11" class="mim-tip-reference" title="Shao, Z., Tumber, A., Maynes, J., Tavares, E., Kannu, P., Heon, E., Vincent, A. <strong>Unique retinal signaling defect in GNB5-related disease.</strong> Docum. Ophthal. 140: 273-277, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31720979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31720979</a>] [<a href="https://doi.org/10.1007/s10633-019-09735-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31720979">Shao et al. (2020)</a> identified homozygosity for a nonsense mutation in the GNB5 gene (Y344X; <a href="#0010">604447.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31720979" 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 5 children from 4 families with LDMLS1, <a href="#7" class="mim-tip-reference" title="Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others. <strong>The epileptology of GNB5 encephalopathy.</strong> Epilepsia 60: e121-e127, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31631344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31631344</a>] [<a href="https://doi.org/10.1111/epi.16372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31631344">Poke et al. (2019)</a> identified homozygosity for mutations in the GNB5 gene (see, e.g., <a href="#0005">604447.0005</a>, <a href="#0010">604447.0010</a>, and <a href="#0011">604447.0011</a>). The variants segregated with disease in all families and were either not found or were present at very low minor allele frequency in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31631344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Pakistani brothers, 18 and 22 years of age, with severe global cognitive and motor delay, nocturnal seizures, cortical visual impairment, and sick sinus syndrome, <a href="#18" class="mim-tip-reference" title="Yazdani, S., Badjatiya, A., Dorrani, N., Lee, H., Grody, W. W., Nelson, S. F., Dipple, K. M. <strong>Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.</strong> Molec. Genet. Metab. Rep. 23: 100582, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32280589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32280589</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2020.100582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32280589">Yazdani et al. (2020)</a> identified homozygosity for the previously reported Y344X mutation (<a href="#0005">604447.0005</a>) in the GNB5 gene. Their mother was heterozygous for the mutation; DNA was unavailable from their father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32280589" 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 6-month-old Han Chinese boy with LDMLS1, <a href="#12" class="mim-tip-reference" title="Tang, M., Wang, Y., Xu, Y., Tong, W., Jin, D., Yang, X. A. <strong>IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.</strong> J. Hum. Genet. 65: 627-631, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32203251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32203251</a>] [<a href="https://doi.org/10.1038/s10038-020-0742-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32203251">Tang et al. (2020)</a> identified compound heterozygosity for a previously reported nonsense mutation (Y344X; <a href="#0010">604447.0010</a>) and a missense mutation (C153Y; <a href="#0012">604447.0012</a>). The missense substitution was inherited from his mother, whereas the nonsense mutation arose de novo; neither was found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32203251" 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>Lodder-Merla Syndrome Type 2 with Developmental Delay and with or without Cardiac Arrhythmia (LDMLS2)</em></strong></p><p>
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In 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with Lodder-Merla syndrome type 2 with developmental delay and cardiac arrhythmia (LDMLS2; <a href="/entry/617182">617182</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous missense mutation in the GNB5 gene (S81L; <a href="#0006">604447.0006</a>). Functional studies of the variant were not performed. These patients were part of a cohort of 9 patients from 6 families who were found to have GNB5 mutations: those with truncating mutations had a more severe phenotype (LDMLS1) than those with the missense mutation, suggesting a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, <a href="#10" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, leading to weaker activity of RGS complexes and a decreased ability to deactivate DRD2-mediated signaling by dopamine. <a href="#10" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> noted that knockdown of the Gnb5 gene in C. elegans results in increased locomotor activity (<a href="#8" class="mim-tip-reference" title="Porter, M. Y., Xie, K., Pozharski, E., Koelle, M. R., Martemyanov, K. A. <strong>A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins.</strong> J. Biol. Chem. 285: 41100-41112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20959458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20959458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20959458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M110.163600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20959458">Porter et al., 2010</a>), and that knockdown of the mouse ortholog results in hyperactivity and abnormal motor coordination (<a href="#17" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al., 2012</a>), making the gene a candidate for attention deficit-hyperactivity disorder (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21766168+20959458+27677260" 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 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, <a href="#6" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al. (2018)</a> identified compound heterozygosity for 2 previously reported mutations in the GNB5 gene: an S81L substitution (<a href="#0006">604447.0006</a>) and a 5-bp deletion (<a href="#0008">604447.0008</a>). Her unaffected parents were heterozygous for the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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 'flailer' (flr) mouse exhibits a phenotype consisting of frequent falling, convulsive limb movements (leg flailing), and ataxia persistent into adulthood. <a href="#3" class="mim-tip-reference" title="Jones, J. M., Huang, J.-D., Mermall, V., Hamilton, B. A., Mooseker, M. S., Escayg, A., Copeland, N. G., Jenkins, N. A., Meisler, M. H. <strong>The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.</strong> Hum. Molec. Genet. 9: 821-828, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749990</a>] [<a href="https://doi.org/10.1093/hmg/9.5.821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749990">Jones et al. (2000)</a> determined that the flailer mouse expresses a novel gene combining the promoter and first 2 exons of Gnb5 with the C-terminal exons of the closely linked myosin-5A (MyoVA) gene (Myo5a; <a href="/entry/160777">160777</a>). Biochemical and genetic studies indicated that the flailer protein, which is expressed predominantly in brain, competes with wildtype MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wildtype proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with nonhomologous recombination as the mutational mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749990" 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="#19" class="mim-tip-reference" title="Zhang, J.-H., Pandey, M., Seigneur, E. M., Panicker, L. M., Koo, L., Schwartz, O. M., Chen, W., Chen, C.-K., Simonds, W. F. <strong>Knockout of G protein beta-5 impairs brain development and causes multiple neurologic abnormalities in mice.</strong> J. Neurochem. 119: 544-554, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21883221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21883221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21883221[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/10.1111/j.1471-4159.2011.07457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21883221">Zhang et al. (2011)</a> found that homozygous Gnb5-knockout mice were runty at birth and exhibited persistent smaller body size compared with wildtype littermates. Knockout mice showed significantly delayed or absent surface righting reflex, and markedly abnormal placing responses, indicating impaired neurobehavioral development. Mice lacking Gnb5 also displayed abnormal gait, balance, gross motor coordination, and motor learning, as well as hyperactivity. Consistent with these findings, the authors confirmed defects in cerebellar and hippocampal development in Gnb5-knockout mice. Multiple genes were dysregulated in brains of knockout mice. <a href="#19" class="mim-tip-reference" title="Zhang, J.-H., Pandey, M., Seigneur, E. M., Panicker, L. M., Koo, L., Schwartz, O. M., Chen, W., Chen, C.-K., Simonds, W. F. <strong>Knockout of G protein beta-5 impairs brain development and causes multiple neurologic abnormalities in mice.</strong> J. Neurochem. 119: 544-554, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21883221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21883221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21883221[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/10.1111/j.1471-4159.2011.07457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21883221">Zhang et al. (2011)</a> concluded that GNB5 regulates dendritic arborization and/or synapse formation during development, partly by regulating gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21883221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al. (2012)</a> found that Gnb5-null mice had hyperactivity and motor learning deficits, as well as a paradoxical adaptation to a novel environment. Gnb5-null mouse brains had lower levels of extracellular dopamine as well as slowed dopamine release and reuptake compared to wildtype. There was also increased sensitivity to inhibitory pre- and postsynaptic G-protein coupled receptor signaling, consistent with the loss of the inhibitory effects of Gnb5/RGS on other receptor signaling pathways. Pharmacologic treatment with monoamine reuptake inhibitors were ineffective in reducing hyperactivity; however, NMDA receptor blockade completely reversed hyperactivity, suggesting that the mutant mice had changes in glutamatergic signaling. The findings indicated that Gnb5-RGS complexes serve as key modulators of signaling pathways that control neuronal excitability and motor activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21766168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> used CRISPR/Cas9 genome editing to generate complete loss of gnb5 function in zebrafish; mutant zebrafish had impaired swimming activity, remained small, and died 7 to 14 days post-fertilization, likely due to an inability to feed. Treatment of mutant larvae with carbachol, a parasympathomimetic compound that activates the GNB5/RGS/GIRK (G protein-coupled inward rectifier potassium) channel pathway, resulted in a strong decrease in heart rate compared to controls. Treatment with a sympathetic agonist resulted in an increased heart rate similar to controls. These findings indicated that loss of gnb5 caused a loss of negative regulation of the cardiac GIRK channel and parasympathetic control, without effects on sympathetic control. Mutant larvae were predominantly unresponsive to repeated tactile stimulation, apparently due to neurologic deficits, not muscle dysfunction, and showed impaired optokinetic responses, also with normal eye muscle function. The findings indicated that Gnb5 is important for neuronal signaling and autonomic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604447[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
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<p>In 2 sisters of Italian descent (family A) with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified compound heterozygous mutations in the GNB5 gene: a c.249G-A transition (c.249G-A, NM_006578.3) at the last nucleotide of exon 2, resulting in a splice site mutation, and a c.994C-T transition, resulting in an arg332-to-ter (R332X; <a href="#0002">604447.0002</a>) substitution. Analysis of patient cells showed that the c.249G-A variant caused aberrant splicing with the inclusion of intron 2, and was predicted to encode a truncated protein (Asp84Valfs52Ter). The transcripts of both alleles were demonstrated to result in nonsense-mediated mRNA decay, consistent with a complete loss of function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the found in the dbSNP (build 138) database; the c.249G-A mutation was not found in the ExAC database, whereas the R332X was found at a low frequency (8.24 x 10(-6)) in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
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<p>For discussion of the c.994C-T transition (c.994C-T, NM_006578.3) in the GNB5 gene, resulting in an arg332-to-ter (R332X) substitution that was found in compound heterozygous state in 2 sisters with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>) by <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a>, see <a href="#0001">604447.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
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<p>In a 6-year-old girl, born of consanguineous parents of Jordanian descent (family B), with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous G-to-T transversion in intron 2 of the GNB5 gene (c.249+1G-T, NM_006578.3), resulting in a splice site alteration and predicted to encode a truncated protein (Asp84Leufs31Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 138) or ExAC databases. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs, born of consanguineous parents of Puerto Rican descent (family C), with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous A-to-G transition in intron 2 of the GNB5 gene (c.249+3A-G, NM_006578.3), resulting in a splice site alteration and predicted to encode a truncated protein (Asp84Valfs31Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138) or ExAC databases. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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> rs749597091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749597091;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/rs749597091?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=rs749597091" 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=rs749597091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 12-year-old girl of Indian descent (family D) with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous c.906C-G transversion (c.906C-G, NM_006578.3) in the GNB5 gene, resulting in a tyr302-to-ter (Y302X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 138) database, but was found at a low frequency (8.26 x 10(-6)) in the ExAC database. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 3-year-old Pakistani boy (patient 2) with infantile spasms and bradycardia with 6.9-second pauses, who was nonverbal and nonambulatory, <a href="#7" class="mim-tip-reference" title="Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others. <strong>The epileptology of GNB5 encephalopathy.</strong> Epilepsia 60: e121-e127, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31631344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31631344</a>] [<a href="https://doi.org/10.1111/epi.16372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31631344">Poke et al. (2019)</a> identified homozygosity for the previously reported Y302X mutation in the GNB5 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31631344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Pakistani brothers, 18 and 22 years of age, with severe global cognitive and motor delay, nocturnal seizures, cortical visual impairment, and sick sinus syndrome, <a href="#18" class="mim-tip-reference" title="Yazdani, S., Badjatiya, A., Dorrani, N., Lee, H., Grody, W. W., Nelson, S. F., Dipple, K. M. <strong>Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.</strong> Molec. Genet. Metab. Rep. 23: 100582, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32280589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32280589</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2020.100582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32280589">Yazdani et al. (2020)</a> identified homozygosity for a c.1032C-G transversion (c.1032C-G, NM_016194.3) in the GNB5 gene, resulting in a Y344X substitution in the GNB5 gene. Their mother was heterozygous for the mutation; DNA was unavailable from their father. <a href="#7" class="mim-tip-reference" title="Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others. <strong>The epileptology of GNB5 encephalopathy.</strong> Epilepsia 60: e121-e127, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31631344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31631344</a>] [<a href="https://doi.org/10.1111/epi.16372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31631344">Poke et al. (2019)</a> noted that the base positions c.906C and c.1032C are equivalent in the transcripts NM_006578.3 and NM_016194.3, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32280589+31631344" 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 LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA</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> rs761399728 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761399728;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/rs761399728?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=rs761399728" 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=rs761399728" 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=RCV000239906 OR RCV000258832 OR RCV000488987 OR RCV000709974 OR RCV000989338 OR RCV002518551" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239906, RCV000258832, RCV000488987, RCV000709974, RCV000989338, RCV002518551" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239906...</a>
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<p>In 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with Lodder-Merla syndrome type 2 with developmental delay and cardiac arrhythmia (LDMLS2; <a href="/entry/617182">617182</a>) <a href="#5" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous c.242C-T transition (c.242C-T, NM_006578.3) in exon 2 of the GNB5 gene, resulting in a ser81-to-leu (S81L) substitution at a highly conserved residue in the first WD40 domain in a beta-strand close to the central pore. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the dbSNP (build 138) database; it was present at a frequency of less than 5 x 10(-5) in the ExAC database (6 in 121,000), and 4.3 x 10(-4) in Latinos (5 in 11,574). Among individuals from Morocco, the prevalence of the variant was 1 in 1,260 (7.94 x 10(-4)). Molecular modeling suggested that the S81L substitution could induce localized structural changes that could impair both the central pore and the binding kinetics to regulator proteins, possibly leading to impaired function. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, <a href="#10" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project database or in 2,379 Saudi exomes. Patient cells showed decreased levels of the mutant protein, suggesting instability, and transfection studies in HEK293 cells showed that the mutation also had a detrimental effect on the folding or stability of R7 RGS complexes. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, resulting in weaker activity of RGS complexes and a decreased ability to deactivate DRD2-mediated signaling by dopamine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27677260" 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 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, <a href="#6" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al. (2018)</a> identified compound heterozygosity for mutations in exon 2 of the GNB5 gene: the S81L substitution and a 5-bp deletion (<a href="#0008">604447.0008</a>). Her unaffected parents were heterozygous for the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 10-year-old girl and her 2-year-old affected second cousin from a consanguineous Turkish family with early infantile epileptic encephalopathy, severe neurologic developmental delay, nystagmus, retinal degeneration, cardiac conduction disorder, and premature sudden death (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#13" class="mim-tip-reference" title="Turkdogan, D., Usluer, S., Akalin, F., Agyuz, U., Aslan, E. S. <strong>Familial early infantile epileptic encephalopathy and cardiac conduction disorder: A rare cause of SUDEP in infancy.</strong> Seizure 50: 171-172, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28697420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28697420</a>] [<a href="https://doi.org/10.1016/j.seizure.2017.06.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28697420">Turkdogan et al. (2017)</a> identified homozygosity for a 1-bp deletion (c.355delG) in the GNB5 gene, causing a frameshift predicted to result in a premature termination codon (Ala119ProfsTer16). Both sets of unaffected parents and 2 unaffected sisters of the proband were heterozygous for the deletion; DNA was unavailable from the proband's 4 affected sibs who had died. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28697420" 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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">rs1085307675 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1085307675;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=rs1085307675" 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=rs1085307675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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In a 2-year-old boy with severe developmental delay and bradycardia (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#14" class="mim-tip-reference" title="Vernon, H., Cohen, J., De Nittis, P., Fatemi, A., McClellan, R., Goldstein, A., Malerba, N., Guex, N., Reymond, A., Merla, G. <strong>Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.</strong> Clin. Genet. 93: 1254-1256, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29368331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29368331</a>] [<a href="https://doi.org/10.1111/cge.13194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29368331">Vernon et al. (2018)</a> identified compound heterozygosity for mutations in the GNB5 gene: a 5-bp deletion (c.222_226delTAAGA, NM_006578.3), causing a frameshift predicted to result in a premature termination codon (Asp74GlufsTer52), and a c.737G-A transition, resulting in an arg246-to-gln (R246W; <a href="#0009">604447.0009</a>) substitution at a conserved residue on the binding surface of the central pore. The authors noted that the c.737G-A variant, involving the last nucleotide of exon 7, might alternatively affect splicing. The proband's unaffected parents were each heterozygous for 1 of the variants, neither of which was found in the ExAC database. The proband was nonverbal, could not sit independently, and made minimal voluntary movements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29368331" 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>LDMLS2</em></strong></p><p>
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In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction (LDMLS2; <a href="/entry/617182">617182</a>) <a href="#6" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al. (2018)</a> identified compound heterozygosity for mutations in exon 2 of the GNB5 gene: a previously reported S81L substitution (<a href="#0006">604447.0006</a>) and a 5-bp deletion (c.222_226delTAAGA). Her unaffected parents were heterozygous for the variants. The proband spoke 12 words and used sign language, and was ambulatory with a wide-based gait. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003321476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003321476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003321476</a>
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<p>For discussion of the c.737G-A transition (c.737G-A, NM_006578.3) in the GNB5 gene, resulting in an arg246-to-gln (R246Q) substitution, that was found in compound heterozygous state in a 2-year-old boy with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>) by <a href="#14" class="mim-tip-reference" title="Vernon, H., Cohen, J., De Nittis, P., Fatemi, A., McClellan, R., Goldstein, A., Malerba, N., Guex, N., Reymond, A., Merla, G. <strong>Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.</strong> Clin. Genet. 93: 1254-1256, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29368331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29368331</a>] [<a href="https://doi.org/10.1111/cge.13194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29368331">Vernon et al. (2018)</a>, see <a href="#0008">604447.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29368331" 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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> rs749597091 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749597091;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/rs749597091?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=rs749597091" 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=rs749597091" 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=RCV000519052 OR RCV001250226" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000519052, RCV001250226" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000519052...</a>
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<p>In a 3-year-old girl of South Asian descent with global developmental delay, seizures, severe bradycardia, and retinopathy (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#11" class="mim-tip-reference" title="Shao, Z., Tumber, A., Maynes, J., Tavares, E., Kannu, P., Heon, E., Vincent, A. <strong>Unique retinal signaling defect in GNB5-related disease.</strong> Docum. Ophthal. 140: 273-277, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31720979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31720979</a>] [<a href="https://doi.org/10.1007/s10633-019-09735-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31720979">Shao et al. (2020)</a> identified homozygosity for a c.906C-A transversion (c.906C-A, NM_006578.3) in the GNB5 gene, resulting in a tyr302-to-ter (Y302X) substitution in the short GNB5 transcript. The mutation was designated Y344X in the long transcript (c.1032C-A, NM_016194.3). The mutation status of her parents was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31720979" 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 3-year-old girl (patient 5) with profound intellectual disability who was nonverbal and nonambulatory, and had seizures, sinus bradycardia with 4.2-second pauses, nystagmus, and retinopathy, <a href="#7" class="mim-tip-reference" title="Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others. <strong>The epileptology of GNB5 encephalopathy.</strong> Epilepsia 60: e121-e127, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31631344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31631344</a>] [<a href="https://doi.org/10.1111/epi.16372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31631344">Poke et al. (2019)</a> identified homozygosity for the Y302X (c.906C-A) substitution in the GNB5 gene. Her parents were heterozygous for the mutation, which was not found in the ExAC database, but was present in 1 allele in the gnomAD database (minor allele frequency, 0.000003982). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31631344" 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 6-month-old Han Chinese boy with LDMLS1, <a href="#12" class="mim-tip-reference" title="Tang, M., Wang, Y., Xu, Y., Tong, W., Jin, D., Yang, X. A. <strong>IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.</strong> J. Hum. Genet. 65: 627-631, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32203251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32203251</a>] [<a href="https://doi.org/10.1038/s10038-020-0742-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32203251">Tang et al. (2020)</a> identified compound heterozygous mutation in the GNB gene: the previously reported Y344X (c.1032C-A, NM_016194) mutation and a c.458G-A transition, resulting in a cys153-to-tyr (C153Y; <a href="#0012">604447.0012</a>) substitution at a highly conserved residue within the first WD domain. The missense substitution was inherited from his mother, whereas the nonsense mutation arose de novo; neither was found in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32203251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 Algerian sisters (patients 3 and 4) with profound intellectual disability and bradycardia, who were nonverbal and nonambulatory (LDMLS1; <a href="/entry/617173">617173</a>), <a href="#7" class="mim-tip-reference" title="Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others. <strong>The epileptology of GNB5 encephalopathy.</strong> Epilepsia 60: e121-e127, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31631344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31631344</a>] [<a href="https://doi.org/10.1111/epi.16372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31631344">Poke et al. (2019)</a> identified homozygosity for a c.242C-A transversion (c.242C-A, NM_006578.3) in the short transcript of the GNB5 gene, resulting in a ser81-to-ter (S81X) substitution. The mutation was designated c.368C-A/S123X in the long isoform (c.368C-A, NM_016194). Their first-cousin parents were heterozygous for the mutation, which was not found in the ExAC or gnomAD databases. The older sister (patient 3) died in her sleep at age 13 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31631344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003321475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003321475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003321475</a>
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<p>For discussion of the c.458G-A transition (c.458G-A, NM_016194) in the GNB5 gene, resulting in a cys153-to-tyr (C153Y) substitution, that was found in compound heterozygous state in a 6-month-old Han Chinese boy with Lodder-Merla syndrome type 1 (LDMLS1; <a href="/entry/617173">617173</a>) by <a href="#12" class="mim-tip-reference" title="Tang, M., Wang, Y., Xu, Y., Tong, W., Jin, D., Yang, X. A. <strong>IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.</strong> J. Hum. Genet. 65: 627-631, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32203251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32203251</a>] [<a href="https://doi.org/10.1038/s10038-020-0742-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32203251">Tang et al. (2020)</a>, see <a href="#0010">604447.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32203251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1016/s0167-4889(98)00017-2" target="_blank">Full Text</a>]
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<strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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=27523599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2016.06.025" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank">Full Text</a>]
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Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others.
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[<a href="https://doi.org/10.1111/epi.16372" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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=27677260" 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/10.1186/s13059-016-1061-6" target="_blank">Full Text</a>]
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<a id="Shao2020" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1007/s10633-019-09735-1" target="_blank">Full Text</a>]
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<a id="Tang2020" class="mim-anchor"></a>
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Tang, M., Wang, Y., Xu, Y., Tong, W., Jin, D., Yang, X. A.
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<strong>IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32203251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32203251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32203251" 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/s10038-020-0742-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.seizure.2017.06.019" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29368331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29368331</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29368331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13194" target="_blank">Full Text</a>]
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Watson, A. J., Aragay, A. M., Slepak, V. Z., Simon, M. I.
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<strong>A novel form of the G protein beta subunit G-beta-5 is specifically expressed in the vertebrate retina.</strong>
|
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J. Biol. Chem. 271: 28154-28160, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8910430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8910430</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8910430" 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/10.1074/jbc.271.45.28154" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Watson1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watson, A. J., Katz, A., Simon, M. I.
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<strong>A fifth member of the mammalian G-protein beta subunit family: expression in brain and activation of the beta-2 isotype of phospholipase C.</strong>
|
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J. Biol. Chem. 269: 22150-22156, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8071339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8071339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8071339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Xie2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A.
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<strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong>
|
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Psychopharmacology 219: 823-834, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[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=21766168" 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/10.1007/s00213-011-2409-y" target="_blank">Full Text</a>]
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Yazdani2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yazdani, S., Badjatiya, A., Dorrani, N., Lee, H., Grody, W. W., Nelson, S. F., Dipple, K. M.
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<strong>Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.</strong>
|
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Molec. Genet. Metab. Rep. 23: 100582, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32280589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32280589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32280589" 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.ymgmr.2020.100582" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Zhang2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, J.-H., Pandey, M., Seigneur, E. M., Panicker, L. M., Koo, L., Schwartz, O. M., Chen, W., Chen, C.-K., Simonds, W. F.
|
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<strong>Knockout of G protein beta-5 impairs brain development and causes multiple neurologic abnormalities in mice.</strong>
|
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J. Neurochem. 119: 544-554, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21883221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21883221</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21883221[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=21883221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1471-4159.2011.07457.x" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/16/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 07/16/2018<br>Bao Lige - updated : 07/16/2018<br>Cassandra L. Kniffin - updated : 11/04/2016<br>Patricia A. Hartz - updated : 3/14/2007<br>Victor A. McKusick - updated : 6/25/2003<br>Joanna S. Amberger - updated : 4/19/2002<br>George E. Tiller - updated : 4/25/2000
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 1/19/2000
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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joanna : 08/16/2023<br>alopez : 08/16/2023<br>mgross : 07/16/2018<br>mgross : 07/16/2018<br>carol : 01/31/2018<br>carol : 11/09/2016<br>ckniffin : 11/04/2016<br>carol : 09/28/2016<br>wwang : 03/20/2007<br>terry : 3/14/2007<br>tkritzer : 6/27/2003<br>tkritzer : 6/25/2003<br>joanna : 4/19/2002<br>alopez : 4/25/2000<br>carol : 1/19/2000
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604447
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-5; GNB5
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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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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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GB5
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GNB5</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1186711002;
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</span>
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<div>
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<br />
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 15q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:52,115,100-52,191,392 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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15q21.2
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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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Lodder-Merla syndrome, type 1, with impaired intellectual development and cardiac arrhythmia
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
617173
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia
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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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|
617182
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The GNB5 gene encodes a beta subunit of heterotrimeric GTP-binding proteins (G proteins). GNB5 forms complexes with members of the R7 regulator family of RGS proteins (see, e.g., RGS7, 602517 and RGS9, 604067) as well as with R7-binding protein (RGS7BP; 610890), and is essential for the structural integrity and proteolytic stability of R7 RGS complexes, which serve as negative regulators of G protein-coupled receptor (GPCR) signaling. GNB5 is expressed in the brain and plays a role in neurotransmitter signaling, including via the dopamine D2 receptor (DRD2; 126450) (summary by Xie et al., 2012 and Shamseldin et al., 2016). GNB5 also interacts with G protein-coupled inward rectifier potassium channels (GIRK; see, e.g., GIRK2, 600877) involved in the hyperpolarization of cell membranes (summary by Lodder et al., 2016). </p><p>For structural information about G proteins, see 600874.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a degenerate PCR approach to screen a human brain cDNA library, Jones et al. (1998) cloned the beta-5 subunit, symbolized GNB5, of G protein. In contrast to beta subunits 1 through 4, which are at least 83% homologous, GNB5 is only 50% homologous to the other beta subunits. On the other hand, the predicted 353-amino acid protein sequence is 99.4% homologous to the mouse beta-5 protein, with only 2 conservative amino acid differences. Northern blot analysis revealed that mouse Gnb5 is expressed predominantly in brain (Watson et al., 1994), whereas human GNB5 is expressed at high levels not only in brain but also in pancreas, kidney, and heart (Jones et al., 1998), as a major 3.0- and minor 2.0- and 9.0-kb transcripts. Within the brain, Jones et al. (1998) detected highest expression in cerebellum, cerebral cortex, occipital pole, frontal lobe, temporal lobe, and caudate putamen, and lowest expression in corpus callosum and spinal cord. </p><p>Watson et al. (1996) reported the cloning of a retina-specific cDNA, termed G-beta-5L, in the mouse, which is identical to GNB5 except for an additional 126-bp 5-prime exon. </p>
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Rosskopf et al. (2003) determined that the GNB5 gene contains 12 exons. The first exon is noncoding and exons 2 and 3 contain alternate ATG translational start codons. </p>
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</span>
|
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Gross (2018) mapped the GNB5 gene to chromosome 15q21.2 based on an alignment of the GNB5 sequence (GenBank BC013997) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</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>GNB5 interacts with regulator of G protein signaling (RGS) proteins containing the G protein gamma-like (GGL) domain: RGS6 (603894), RGS7 (602517), RGS9 (604067), and RGS11 (603895). Chen et al. (2003) presented data indicating that GNB5 and GGL domain-containing RGS proteins are obligate partners and supporting the notion that GNB5 functions as a component of the GTPase-accelerating protein (GAP) complex. </p><p>In mouse hippocampus and striatum, Xie et al. (2012) found expression of Gnb5 in pre- and postsynaptic regions and in dendritic shafts and spines of neurons. Localization was observed both at the plasma membrane and in intracellular regions, as well as at the active zone of the axonal terminals. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Lodder-Merla Syndrome Type 1 with Impaired Intellectual Development and Cardiac Arrhythmia</em></strong></p><p>
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In 6 patients from 4 unrelated families with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), Lodder et al. (2016) identified homozygous or compound heterozygous truncating mutations in the GNB5 gene (604447.0001-604447.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants were not performed; studies of patient cells, performed only in 1 family (family A) with compound heterozygous truncating variants, demonstrated that both alleles were subject to nonsense-mediated mRNA, resulting in a putative complete loss of function. </p><p>In a consanguineous Turkish family in which 5 sibs and their second cousin had LDMLS1, Turkdogan et al. (2017) identified homozygosity for a 1-bp deletion in the GNB5 gene (604447.0007) that segregated with disease in the family. </p><p>In a 2-year-old boy with severe developmental delay and bradycardia, Vernon et al. (2018) identified compound heterozygosity for a 5-bp deletion (604447.0008) and a missense mutation (R246Q; 604447.0009) in the GNB5 gene. The mutations segregated with disease in the family and were not found in the ExAC database. </p><p>In a 3-year-old girl of South Asian descent with global developmental delay, seizures, severe bradycardia, and retinopathy, Shao et al. (2020) identified homozygosity for a nonsense mutation in the GNB5 gene (Y344X; 604447.0010). </p><p>In 5 children from 4 families with LDMLS1, Poke et al. (2019) identified homozygosity for mutations in the GNB5 gene (see, e.g., 604447.0005, 604447.0010, and 604447.0011). The variants segregated with disease in all families and were either not found or were present at very low minor allele frequency in public variant databases. </p><p>In 2 Pakistani brothers, 18 and 22 years of age, with severe global cognitive and motor delay, nocturnal seizures, cortical visual impairment, and sick sinus syndrome, Yazdani et al. (2020) identified homozygosity for the previously reported Y344X mutation (604447.0005) in the GNB5 gene. Their mother was heterozygous for the mutation; DNA was unavailable from their father. </p><p>In a 6-month-old Han Chinese boy with LDMLS1, Tang et al. (2020) identified compound heterozygosity for a previously reported nonsense mutation (Y344X; 604447.0010) and a missense mutation (C153Y; 604447.0012). The missense substitution was inherited from his mother, whereas the nonsense mutation arose de novo; neither was found in public variant databases. </p><p><strong><em>Lodder-Merla Syndrome Type 2 with Developmental Delay and with or without Cardiac Arrhythmia (LDMLS2)</em></strong></p><p>
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In 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with Lodder-Merla syndrome type 2 with developmental delay and cardiac arrhythmia (LDMLS2; 617182), Lodder et al. (2016) identified a homozygous missense mutation in the GNB5 gene (S81L; 604447.0006). Functional studies of the variant were not performed. These patients were part of a cohort of 9 patients from 6 families who were found to have GNB5 mutations: those with truncating mutations had a more severe phenotype (LDMLS1) than those with the missense mutation, suggesting a genotype/phenotype correlation. </p><p>In 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, Shamseldin et al. (2016) identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, leading to weaker activity of RGS complexes and a decreased ability to deactivate DRD2-mediated signaling by dopamine. Shamseldin et al. (2016) noted that knockdown of the Gnb5 gene in C. elegans results in increased locomotor activity (Porter et al., 2010), and that knockdown of the mouse ortholog results in hyperactivity and abnormal motor coordination (Xie et al., 2012), making the gene a candidate for attention deficit-hyperactivity disorder (see ANIMAL MODEL). </p><p>In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, Malerba et al. (2018) identified compound heterozygosity for 2 previously reported mutations in the GNB5 gene: an S81L substitution (604447.0006) and a 5-bp deletion (604447.0008). Her unaffected parents were heterozygous for the variants. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The 'flailer' (flr) mouse exhibits a phenotype consisting of frequent falling, convulsive limb movements (leg flailing), and ataxia persistent into adulthood. Jones et al. (2000) determined that the flailer mouse expresses a novel gene combining the promoter and first 2 exons of Gnb5 with the C-terminal exons of the closely linked myosin-5A (MyoVA) gene (Myo5a; 160777). Biochemical and genetic studies indicated that the flailer protein, which is expressed predominantly in brain, competes with wildtype MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wildtype proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with nonhomologous recombination as the mutational mechanism. </p><p>Zhang et al. (2011) found that homozygous Gnb5-knockout mice were runty at birth and exhibited persistent smaller body size compared with wildtype littermates. Knockout mice showed significantly delayed or absent surface righting reflex, and markedly abnormal placing responses, indicating impaired neurobehavioral development. Mice lacking Gnb5 also displayed abnormal gait, balance, gross motor coordination, and motor learning, as well as hyperactivity. Consistent with these findings, the authors confirmed defects in cerebellar and hippocampal development in Gnb5-knockout mice. Multiple genes were dysregulated in brains of knockout mice. Zhang et al. (2011) concluded that GNB5 regulates dendritic arborization and/or synapse formation during development, partly by regulating gene expression. </p><p>Xie et al. (2012) found that Gnb5-null mice had hyperactivity and motor learning deficits, as well as a paradoxical adaptation to a novel environment. Gnb5-null mouse brains had lower levels of extracellular dopamine as well as slowed dopamine release and reuptake compared to wildtype. There was also increased sensitivity to inhibitory pre- and postsynaptic G-protein coupled receptor signaling, consistent with the loss of the inhibitory effects of Gnb5/RGS on other receptor signaling pathways. Pharmacologic treatment with monoamine reuptake inhibitors were ineffective in reducing hyperactivity; however, NMDA receptor blockade completely reversed hyperactivity, suggesting that the mutant mice had changes in glutamatergic signaling. The findings indicated that Gnb5-RGS complexes serve as key modulators of signaling pathways that control neuronal excitability and motor activity. </p><p>Lodder et al. (2016) used CRISPR/Cas9 genome editing to generate complete loss of gnb5 function in zebrafish; mutant zebrafish had impaired swimming activity, remained small, and died 7 to 14 days post-fertilization, likely due to an inability to feed. Treatment of mutant larvae with carbachol, a parasympathomimetic compound that activates the GNB5/RGS/GIRK (G protein-coupled inward rectifier potassium) channel pathway, resulted in a strong decrease in heart rate compared to controls. Treatment with a sympathetic agonist resulted in an increased heart rate similar to controls. These findings indicated that loss of gnb5 caused a loss of negative regulation of the cardiac GIRK channel and parasympathetic control, without effects on sympathetic control. Mutant larvae were predominantly unresponsive to repeated tactile stimulation, apparently due to neurologic deficits, not muscle dysfunction, and showed impaired optokinetic responses, also with normal eye muscle function. The findings indicated that Gnb5 is important for neuronal signaling and autonomic function. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, 249G-A
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<br />
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SNP: rs886041054,
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ClinVar: RCV000258840
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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 sisters of Italian descent (family A) with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), Lodder et al. (2016) identified compound heterozygous mutations in the GNB5 gene: a c.249G-A transition (c.249G-A, NM_006578.3) at the last nucleotide of exon 2, resulting in a splice site mutation, and a c.994C-T transition, resulting in an arg332-to-ter (R332X; 604447.0002) substitution. Analysis of patient cells showed that the c.249G-A variant caused aberrant splicing with the inclusion of intron 2, and was predicted to encode a truncated protein (Asp84Valfs52Ter). The transcripts of both alleles were demonstrated to result in nonsense-mediated mRNA decay, consistent with a complete loss of function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the found in the dbSNP (build 138) database; the c.249G-A mutation was not found in the ExAC database, whereas the R332X was found at a low frequency (8.24 x 10(-6)) in the ExAC 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>.0002 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, ARG332TER
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<br />
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SNP: rs773902879,
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gnomAD: rs773902879,
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ClinVar: RCV000258819, RCV003319343
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.994C-T transition (c.994C-T, NM_006578.3) in the GNB5 gene, resulting in an arg332-to-ter (R332X) substitution that was found in compound heterozygous state in 2 sisters with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173) by Lodder et al. (2016), see 604447.0001. </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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, IVS2DS, G-T, +1
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<br />
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SNP: rs886041055,
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ClinVar: RCV000258827
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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 6-year-old girl, born of consanguineous parents of Jordanian descent (family B), with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), Lodder et al. (2016) identified a homozygous G-to-T transversion in intron 2 of the GNB5 gene (c.249+1G-T, NM_006578.3), resulting in a splice site alteration and predicted to encode a truncated protein (Asp84Leufs31Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 138) or ExAC databases. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, IVS2DS, A-G, +3
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<br />
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SNP: rs766004901,
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gnomAD: rs766004901,
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ClinVar: RCV000258839, RCV002519027
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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 2 sibs, born of consanguineous parents of Puerto Rican descent (family C), with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), Lodder et al. (2016) identified a homozygous A-to-G transition in intron 2 of the GNB5 gene (c.249+3A-G, NM_006578.3), resulting in a splice site alteration and predicted to encode a truncated protein (Asp84Valfs31Ter). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 138) or ExAC databases. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, TYR302TER, 906C-G
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<br />
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SNP: rs749597091,
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gnomAD: rs749597091,
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ClinVar: RCV000258821, RCV000622353, RCV001387345
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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 girl of Indian descent (family D) with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), Lodder et al. (2016) identified a homozygous c.906C-G transversion (c.906C-G, NM_006578.3) in the GNB5 gene, resulting in a tyr302-to-ter (Y302X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 138) database, but was found at a low frequency (8.26 x 10(-6)) in the ExAC database. The mutation was predicted to result in a loss of function, but functional studies of the variant and studies of patient cells were not performed. </p><p>In a 3-year-old Pakistani boy (patient 2) with infantile spasms and bradycardia with 6.9-second pauses, who was nonverbal and nonambulatory, Poke et al. (2019) identified homozygosity for the previously reported Y302X mutation in the GNB5 gene. </p><p>In 2 Pakistani brothers, 18 and 22 years of age, with severe global cognitive and motor delay, nocturnal seizures, cortical visual impairment, and sick sinus syndrome, Yazdani et al. (2020) identified homozygosity for a c.1032C-G transversion (c.1032C-G, NM_016194.3) in the GNB5 gene, resulting in a Y344X substitution in the GNB5 gene. Their mother was heterozygous for the mutation; DNA was unavailable from their father. Poke et al. (2019) noted that the base positions c.906C and c.1032C are equivalent in the transcripts NM_006578.3 and NM_016194.3, respectively. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA</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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GNB5, SER81LEU
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<br />
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SNP: rs761399728,
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gnomAD: rs761399728,
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ClinVar: RCV000239906, RCV000258832, RCV000488987, RCV000709974, RCV000989338, RCV002518551
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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 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with Lodder-Merla syndrome type 2 with developmental delay and cardiac arrhythmia (LDMLS2; 617182) Lodder et al. (2016) identified a homozygous c.242C-T transition (c.242C-T, NM_006578.3) in exon 2 of the GNB5 gene, resulting in a ser81-to-leu (S81L) substitution at a highly conserved residue in the first WD40 domain in a beta-strand close to the central pore. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the dbSNP (build 138) database; it was present at a frequency of less than 5 x 10(-5) in the ExAC database (6 in 121,000), and 4.3 x 10(-4) in Latinos (5 in 11,574). Among individuals from Morocco, the prevalence of the variant was 1 in 1,260 (7.94 x 10(-4)). Molecular modeling suggested that the S81L substitution could induce localized structural changes that could impair both the central pore and the binding kinetics to regulator proteins, possibly leading to impaired function. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, Shamseldin et al. (2016) identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project database or in 2,379 Saudi exomes. Patient cells showed decreased levels of the mutant protein, suggesting instability, and transfection studies in HEK293 cells showed that the mutation also had a detrimental effect on the folding or stability of R7 RGS complexes. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, resulting in weaker activity of RGS complexes and a decreased ability to deactivate DRD2-mediated signaling by dopamine. </p><p>In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, Malerba et al. (2018) identified compound heterozygosity for mutations in exon 2 of the GNB5 gene: the S81L substitution and a 5-bp deletion (604447.0008). Her unaffected parents were heterozygous for the variants. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, 1-BP DEL, 355G
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<br />
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ClinVar: RCV003321477
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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 10-year-old girl and her 2-year-old affected second cousin from a consanguineous Turkish family with early infantile epileptic encephalopathy, severe neurologic developmental delay, nystagmus, retinal degeneration, cardiac conduction disorder, and premature sudden death (LDMLS1; 617173), Turkdogan et al. (2017) identified homozygosity for a 1-bp deletion (c.355delG) in the GNB5 gene, causing a frameshift predicted to result in a premature termination codon (Ala119ProfsTer16). Both sets of unaffected parents and 2 unaffected sisters of the proband were heterozygous for the deletion; DNA was unavailable from the proband's 4 affected sibs who had died. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND CARDIAC ARRHYTHMIA, INCLUDED
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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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GNB5, 5-BP DEL, 222TAAGA
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<br />
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SNP: rs1085307675,
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ClinVar: RCV000490230, RCV000709973, RCV001770375, RCV003321635
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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 />
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<p><strong><em>LDMLS1</em></strong></p><p>
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In a 2-year-old boy with severe developmental delay and bradycardia (LDMLS1; 617173), Vernon et al. (2018) identified compound heterozygosity for mutations in the GNB5 gene: a 5-bp deletion (c.222_226delTAAGA, NM_006578.3), causing a frameshift predicted to result in a premature termination codon (Asp74GlufsTer52), and a c.737G-A transition, resulting in an arg246-to-gln (R246W; 604447.0009) substitution at a conserved residue on the binding surface of the central pore. The authors noted that the c.737G-A variant, involving the last nucleotide of exon 7, might alternatively affect splicing. The proband's unaffected parents were each heterozygous for 1 of the variants, neither of which was found in the ExAC database. The proband was nonverbal, could not sit independently, and made minimal voluntary movements. </p><p><strong><em>LDMLS2</em></strong></p><p>
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In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction (LDMLS2; 617182) Malerba et al. (2018) identified compound heterozygosity for mutations in exon 2 of the GNB5 gene: a previously reported S81L substitution (604447.0006) and a 5-bp deletion (c.222_226delTAAGA). Her unaffected parents were heterozygous for the variants. The proband spoke 12 words and used sign language, and was ambulatory with a wide-based gait. </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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, ARG246GLN
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<br />
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ClinVar: RCV003321476
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.737G-A transition (c.737G-A, NM_006578.3) in the GNB5 gene, resulting in an arg246-to-gln (R246Q) substitution, that was found in compound heterozygous state in a 2-year-old boy with Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173) by Vernon et al. (2018), see 604447.0008. </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 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, TYR302TER, 906C-A
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<br />
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SNP: rs749597091,
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gnomAD: rs749597091,
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ClinVar: RCV000519052, RCV001250226
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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 3-year-old girl of South Asian descent with global developmental delay, seizures, severe bradycardia, and retinopathy (LDMLS1; 617173), Shao et al. (2020) identified homozygosity for a c.906C-A transversion (c.906C-A, NM_006578.3) in the GNB5 gene, resulting in a tyr302-to-ter (Y302X) substitution in the short GNB5 transcript. The mutation was designated Y344X in the long transcript (c.1032C-A, NM_016194.3). The mutation status of her parents was not reported. </p><p>In a 3-year-old girl (patient 5) with profound intellectual disability who was nonverbal and nonambulatory, and had seizures, sinus bradycardia with 4.2-second pauses, nystagmus, and retinopathy, Poke et al. (2019) identified homozygosity for the Y302X (c.906C-A) substitution in the GNB5 gene. Her parents were heterozygous for the mutation, which was not found in the ExAC database, but was present in 1 allele in the gnomAD database (minor allele frequency, 0.000003982). </p><p>In a 6-month-old Han Chinese boy with LDMLS1, Tang et al. (2020) identified compound heterozygous mutation in the GNB gene: the previously reported Y344X (c.1032C-A, NM_016194) mutation and a c.458G-A transition, resulting in a cys153-to-tyr (C153Y; 604447.0012) substitution at a highly conserved residue within the first WD domain. The missense substitution was inherited from his mother, whereas the nonsense mutation arose de novo; neither was found in public variant databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</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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GNB5, SER81TER
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<br />
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ClinVar: RCV003321474
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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 Algerian sisters (patients 3 and 4) with profound intellectual disability and bradycardia, who were nonverbal and nonambulatory (LDMLS1; 617173), Poke et al. (2019) identified homozygosity for a c.242C-A transversion (c.242C-A, NM_006578.3) in the short transcript of the GNB5 gene, resulting in a ser81-to-ter (S81X) substitution. The mutation was designated c.368C-A/S123X in the long isoform (c.368C-A, NM_016194). Their first-cousin parents were heterozygous for the mutation, which was not found in the ExAC or gnomAD databases. The older sister (patient 3) died in her sleep at age 13 years. </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>.0012 LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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GNB5, CYS153TYR
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<br />
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ClinVar: RCV003321475
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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>For discussion of the c.458G-A transition (c.458G-A, NM_016194) in the GNB5 gene, resulting in a cys153-to-tyr (C153Y) substitution, that was found in compound heterozygous state in a 6-month-old Han Chinese boy with Lodder-Merla syndrome type 1 (LDMLS1; 617173) by Tang et al. (2020), see 604447.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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Chen, C.-K., Eversole-Cire, P., Zhang, H., Mancino, V., Chen, Y.-J., He, W., Wensel, T. G., Simon, M. I.
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<strong>Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit G-beta-5.</strong>
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Proc. Nat. Acad. Sci. 100: 6604-6609, 2003.
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<p class="mim-text-font">
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 7/16/2018.
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Jones, J. M., Huang, J.-D., Mermall, V., Hamilton, B. A., Mooseker, M. S., Escayg, A., Copeland, N. G., Jenkins, N. A., Meisler, M. H.
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<strong>The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.</strong>
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Hum. Molec. Genet. 9: 821-828, 2000.
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<p class="mim-text-font">
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Jones, P. G., Lombardi, S. J., Cockett, M. I.
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<strong>Cloning and tissue distribution of the human G protein beta-5 cDNA.</strong>
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Biochim. Biophys. Acta 1402: 288-291, 1998.
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Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others.
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<strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong>
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Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.
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Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G.
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<strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong>
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Front. Genet. 9: 626, 2018.
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[Full Text: https://doi.org/10.3389/fgene.2018.00626]
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Poke, G., King, C., Muir, A., de Valles-Ibanez, G., Germano, M., Moura de Souza, C. F., Fung, J., Chung, B., Fung, C. W., Mignot, C., Ilea, A., Keren, B., and 11 others.
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<strong>The epileptology of GNB5 encephalopathy.</strong>
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Epilepsia 60: e121-e127, 2019.
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[PubMed: 31631344]
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[Full Text: https://doi.org/10.1111/epi.16372]
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Porter, M. Y., Xie, K., Pozharski, E., Koelle, M. R., Martemyanov, K. A.
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<strong>A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins.</strong>
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J. Biol. Chem. 285: 41100-41112, 2010.
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Rosskopf, D., Nikula, C., Manthey, I., Joisten, M., Frey, U., Kohnen, S., Siffert, W.
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<strong>The human G protein beta-4 subunit: gene structure, expression, G-gamma and effector interaction.</strong>
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FEBS Lett. 544: 27-32, 2003.
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<p class="mim-text-font">
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Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S.
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|
<strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong>
|
|
Genome Biol. 17: 195, 2016. Note: Electronic Article.
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Shao, Z., Tumber, A., Maynes, J., Tavares, E., Kannu, P., Heon, E., Vincent, A.
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<strong>Unique retinal signaling defect in GNB5-related disease.</strong>
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Docum. Ophthal. 140: 273-277, 2020.
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Tang, M., Wang, Y., Xu, Y., Tong, W., Jin, D., Yang, X. A.
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<strong>IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.</strong>
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J. Hum. Genet. 65: 627-631, 2020.
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[PubMed: 32203251]
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Turkdogan, D., Usluer, S., Akalin, F., Agyuz, U., Aslan, E. S.
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<strong>Familial early infantile epileptic encephalopathy and cardiac conduction disorder: A rare cause of SUDEP in infancy.</strong>
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Seizure 50: 171-172, 2017.
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[PubMed: 28697420]
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[Full Text: https://doi.org/10.1016/j.seizure.2017.06.019]
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<p class="mim-text-font">
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Vernon, H., Cohen, J., De Nittis, P., Fatemi, A., McClellan, R., Goldstein, A., Malerba, N., Guex, N., Reymond, A., Merla, G.
|
|
<strong>Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.</strong>
|
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Clin. Genet. 93: 1254-1256, 2018.
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[PubMed: 29368331]
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[Full Text: https://doi.org/10.1111/cge.13194]
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<p class="mim-text-font">
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Watson, A. J., Aragay, A. M., Slepak, V. Z., Simon, M. I.
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<strong>A novel form of the G protein beta subunit G-beta-5 is specifically expressed in the vertebrate retina.</strong>
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J. Biol. Chem. 271: 28154-28160, 1996.
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[PubMed: 8910430]
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[Full Text: https://doi.org/10.1074/jbc.271.45.28154]
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</p>
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<p class="mim-text-font">
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Watson, A. J., Katz, A., Simon, M. I.
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<strong>A fifth member of the mammalian G-protein beta subunit family: expression in brain and activation of the beta-2 isotype of phospholipase C.</strong>
|
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J. Biol. Chem. 269: 22150-22156, 1994.
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[PubMed: 8071339]
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<li>
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<p class="mim-text-font">
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Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A.
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|
<strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong>
|
|
Psychopharmacology 219: 823-834, 2012.
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[PubMed: 21766168]
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[Full Text: https://doi.org/10.1007/s00213-011-2409-y]
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</p>
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</li>
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Yazdani, S., Badjatiya, A., Dorrani, N., Lee, H., Grody, W. W., Nelson, S. F., Dipple, K. M.
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<strong>Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.</strong>
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[PubMed: 32280589]
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[Full Text: https://doi.org/10.1016/j.ymgmr.2020.100582]
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Zhang, J.-H., Pandey, M., Seigneur, E. M., Panicker, L. M., Koo, L., Schwartz, O. M., Chen, W., Chen, C.-K., Simonds, W. F.
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<strong>Knockout of G protein beta-5 impairs brain development and causes multiple neurologic abnormalities in mice.</strong>
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J. Neurochem. 119: 544-554, 2011.
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[PubMed: 21883221]
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[Full Text: https://doi.org/10.1111/j.1471-4159.2011.07457.x]
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