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Entry
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- *138252 - GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2B; GRIN2B
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*138252</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/138252">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000273079;t=ENST00000609686" 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=2904" 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=138252" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000273079;t=ENST00000609686" 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_000834,NM_001413992,NM_001413993,NM_001413994,NM_001413995,XM_005253351" 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_000834" 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=138252" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00697&isoform_id=00697_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/GRIN2B" 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/560547,899435,899437,965064,1899202,4099613,14548162,62087280,109730561,109730563,119616717,167003331,530399104,2054237350,2328705310,2328705369,2328705394,2328705421,2462531536,2462531538,2462531540" 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/Q13224" 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=2904" 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=ENSG00000273079;t=ENST00000609686" 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=GRIN2B" 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=GRIN2B" 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+2904" 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/GRIN2B" 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:2904" 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/2904" 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=chr12&hgg_gene=ENST00000609686.4&hgg_start=13537337&hgg_end=13982134&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:4586" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4586" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/grin2b" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=138252[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=138252[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/GRIN2B/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/ENSG00000273079" 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=GRIN2B" 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=GRIN2B" 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=GRIN2B" 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=GRIN2B&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/PA28980" 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:4586" 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/FBgn0053513.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:95821" 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/GRIN2B#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:95821" 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/2904/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=2904" 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=WBGene00003775;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-061207-27" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2904" 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=GRIN2B&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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138252
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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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GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2B; GRIN2B
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT EPSILON-2; NMDAR2B<br />
|
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NR2B
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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=GRIN2B" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRIN2B</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>
|
|
Cytogenetic location: <a href="/geneMap/12/189?start=-3&limit=10&highlight=189">12p13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:13537337-13982134&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'})">12:13,537,337-13,982,134</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>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616139,613970" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/189?start=-3&limit=10&highlight=189">
|
|
12p13.1
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 27
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616139"> 616139 </a>
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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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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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal dominant 6, with or without seizures
|
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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/613970"> 613970 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated ion channel permeable to Na+, K+, and Ca(2+) and is found at excitatory synapses throughout the brain. NMDA receptors are heterotetramers composed of 2 NMDA receptor-1 (NR1, or GRIN1; <a href="/entry/138249">138249</a>) subunits and 2 NR2 subunits, such as GRIN2B (summary by <a href="#25" class="mim-tip-reference" title="Matta, J. A., Ashby, M. C., Sanz-Clemente, A., Roche, K. W., Isaac, J. T. R. <strong>mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch.</strong> Neuron 70: 339-351, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21521618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21521618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21521618[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.neuron.2011.02.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21521618">Matta et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21521618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By screening a human fetal brain cDNA library with a rat Nmdar2b cDNA, <a href="#14" class="mim-tip-reference" title="Hess, S. D., Daggett, L. P., Crona, J., Deal, C., Lu, C.-C., Urrutia, A., Chavez-Noriega, L., Ellis, S. B., Johnson, E. C., Velicelebi, G. <strong>Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors.</strong> J. Pharm. Exp. Ther. 278: 808-816, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8768735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8768735</a>]" pmid="8768735">Hess et al. (1996)</a> isolated a cDNA encoding NMDAR2B. The sequence of the predicted 1,484-amino acid human protein is 98% and 96% identical to the sequences of the rat and mouse Nmdar2b proteins, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8768735" 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="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> noted that the GRIN2B gene contains 13 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By linkage studies in recombinant inbred lines, <a href="#23" class="mim-tip-reference" title="Madarnas, A. R., Henderson, J. T., Roder, J. C. <strong>The NMDA receptor subunit 2B locus (Nmdar2b) maps to the distal end of murine chromosome 6.</strong> Mammalian Genome 5: 115-116, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8180471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8180471</a>] [<a href="https://doi.org/10.1007/BF00292339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8180471">Madarnas et al. (1994)</a> demonstrated that the Nmdar2b gene is located on mouse chromosome 6 between Rho (<a href="/entry/180380">180380</a>) and Ly49 (<a href="/entry/604274">604274</a>) centromerically and Glb (see <a href="/entry/230500">230500</a>) telomerically. Using both somatic cell hybrids and in situ hybridization, <a href="#24" class="mim-tip-reference" title="Mandich, P., Schito, A. M., Bellone, E., Antonacci, R., Finelli, P., Rocchi, M., Ajmar, F. <strong>Mapping of the human NMDAR2B receptor subunit gene (GRIN2B) to chromosome 12p12.</strong> Genomics 22: 216-218, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959773</a>] [<a href="https://doi.org/10.1006/geno.1994.1366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959773">Mandich et al. (1994)</a> localized the human NMDAR2B gene to 12p12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7959773+8180471" 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="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> noted that the GRIN2B gene maps to chromosome 12p13.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" 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="#14" class="mim-tip-reference" title="Hess, S. D., Daggett, L. P., Crona, J., Deal, C., Lu, C.-C., Urrutia, A., Chavez-Noriega, L., Ellis, S. B., Johnson, E. C., Velicelebi, G. <strong>Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors.</strong> J. Pharm. Exp. Ther. 278: 808-816, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8768735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8768735</a>]" pmid="8768735">Hess et al. (1996)</a> showed that human NMDAR2B functioned as an NMDA receptor when coexpressed with NMDAR1 in Xenopus oocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8768735" 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 the hippocampus and cerebral cortex, the active subunit NMDAR1 is associated with 1 of 2 regulatory epsilon subunits: NMDAR2A (GRIN2A; <a href="/entry/138253">138253</a>) or NMDAR2B. <a href="#5" class="mim-tip-reference" title="Chen, N., Luo, T., Raymond, L. A. <strong>Subtype-dependence of NMDA receptor channel open probability.</strong> J. Neurosci. 19: 6844-6854, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10436042[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/10.1523/JNEUROSCI.19-16-06844.1999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10436042">Chen et al. (1999)</a> demonstrated a 4-fold increase in mean channel open probability in embryonic kidney cells expressing NMDAR1/NMDAR2A complexes when compared to those expressing NMDAR1/NMDAR2B. They proposed that changes in the relative expression levels of NMDAR2A and NMDAR2B could regulate peak amplitude of NMDA receptor-mediated excitatory postsynaptic potentials and thus modulate the efficiency of synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10436042" 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="#33" class="mim-tip-reference" title="Thomas, K. L., Davis, S., Hunt, S. P., Laroche, S. <strong>Alterations in the expression of specific glutamate receptor subunits following hippocampal LTP in vivo.</strong> Learn. Mem. 3: 197-208, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10456090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10456090</a>] [<a href="https://doi.org/10.1101/lm.3.2-3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10456090">Thomas et al. (1996)</a> demonstrated specific increases in the expression of the NMDAR2B subunit following the induction of hippocampal long-term potentiation (LTP) in the dentate gyrus of rats. This increase was delayed by several days, suggesting that it may be important in the maintenance of LTP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10456090" 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>Experiments with vesicles containing NMDA receptor 2B showed that they are transported along microtubules by KIF17 (<a href="/entry/605037">605037</a>), a neuron-specific molecular motor in neuronal dendrites. <a href="#29" class="mim-tip-reference" title="Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N. <strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong> Science 288: 1796-1802, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846156</a>] [<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846156">Setou et al. (2000)</a> demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10 (<a href="/entry/602414">602414</a>), which is a constituent of a large protein complex including Lin2 (<a href="/entry/300172">300172</a>), Lin7 (<a href="/entry/603380">603380</a>), and the NR2B subunit. <a href="#29" class="mim-tip-reference" title="Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N. <strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong> Science 288: 1796-1802, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846156</a>] [<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846156">Setou et al. (2000)</a> concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10846156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., Schulman, H. <strong>Interaction with the NMDA receptor locks CaMKII in an active conformation.</strong> Nature 411: 801-805, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11459059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11459059</a>] [<a href="https://doi.org/10.1038/35081080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11459059">Bayer et al. (2001)</a> demonstrated that regulated CAMK2 (<a href="/entry/114078">114078</a>) interaction with 2 sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by facilitated CAMK2 response to synaptic calcium, suppression of inhibitory autophosphorylation of CAMK2, and, most, notably, direct generation of sustained calcium/calmodulin-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of calmodulin that may reduce downregulation of NMDA receptor activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11459059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Hardingham, G. E., Fukunaga, Y., Bading, H. <strong>Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.</strong> Nature Neurosci. 5: 405-414, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11953750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11953750</a>] [<a href="https://doi.org/10.1038/nn835" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11953750">Hardingham et al. (2002)</a> reported that synaptic and extrasynaptic NMDA receptors have opposite effects on CREB (<a href="/entry/123810">123810</a>) function, gene regulation, and neuronal survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have antiapoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11953750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Tu, W., Xu, X., Peng, L., Zhong, X., Zhang, W., Soundarapandian, M. M., Balel, C., Wang, M., Jia, N., Zhang, W., Lew, F., Chan, S. L., Chen, Y., Lu, Y. <strong>DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke.</strong> Cell 140: 222-234, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20141836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20141836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20141836[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.cell.2009.12.055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20141836">Tu et al. (2010)</a> found that Dapk1 (<a href="/entry/600831">600831</a>) was responsible for ischemia-induced neuronal cell death in mice. Dapk1 coprecipitated with the NMDA receptor complex and interacted directly with the Nr2b subunit. Ischemia activated Dapk1, and activated Dapk1 serine phosphorylated Nr2b at extrasynaptic sites, leading to injurious Ca(2+) influx and apoptotic cell death. Knockdown of Dapk1 or blocking the Dapk1-Nr2b interaction protected mice against cerebral ischemic damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20141836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To treat stroke without blocking NMDA receptors, <a href="#1" class="mim-tip-reference" title="Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., Tymianski, M. <strong>Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions.</strong> Science 298: 846-850, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12399596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12399596</a>] [<a href="https://doi.org/10.1126/science.1072873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12399596">Aarts et al. (2002)</a> transduced neurons with peptides that disrupted the interaction of NMDA receptors with the postsynaptic density protein PSD95 (<a href="/entry/602887">602887</a>). This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurologic function. <a href="#1" class="mim-tip-reference" title="Aarts, M., Liu, Y., Liu, L., Besshoh, S., Arundine, M., Gurd, J. W., Wang, Y.-T., Salter, M. W., Tymianski, M. <strong>Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions.</strong> Science 298: 846-850, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12399596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12399596</a>] [<a href="https://doi.org/10.1126/science.1072873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12399596">Aarts et al. (2002)</a> concluded that their approach circumvents the negative consequences associated with blocking NMDA receptors and may constitute a practical stroke therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12399596" 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="Kawakami, R., Shinohara, Y., Kato, Y., Sugiyama, H., Shigemoto, R., Ito, I. <strong>Asymmetrical allocation of NMDA receptor epsilon-2 subunits in hippocampal circuitry.</strong> Science 300: 990-994, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12738868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12738868</a>] [<a href="https://doi.org/10.1126/science.1082609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12738868">Kawakami et al. (2003)</a> reported that synaptic distribution of the NMDA receptor GluR-epsilon-2 (NR2B) subunits in the adult mouse hippocampus is asymmetric between the left and right and between the apical and basal dendrites of single neurons. These asymmetric allocations of NR2B subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. <a href="#17" class="mim-tip-reference" title="Kawakami, R., Shinohara, Y., Kato, Y., Sugiyama, H., Shigemoto, R., Ito, I. <strong>Asymmetrical allocation of NMDA receptor epsilon-2 subunits in hippocampal circuitry.</strong> Science 300: 990-994, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12738868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12738868</a>] [<a href="https://doi.org/10.1126/science.1082609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12738868">Kawakami et al. (2003)</a> concluded that their results provided a molecular basis for the structural and functional asymmetry of the mature brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12738868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using hippocampal slice preparations, <a href="#21" class="mim-tip-reference" title="Liu, L., Wong, T. P., Pozza, M. F., Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y. P., Wang, Y. T. <strong>Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.</strong> Science 304: 1021-1024, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15143284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15143284</a>] [<a href="https://doi.org/10.1126/science.1096615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15143284">Liu et al. (2004)</a> showed that selectively blocking NMDA receptors that contain the NR2B subunit abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A (<a href="/entry/138253">138253</a>)-containing NMDA receptors prevented the induction of long-term potentiation without affecting long-term depression production. <a href="#21" class="mim-tip-reference" title="Liu, L., Wong, T. P., Pozza, M. F., Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y. P., Wang, Y. T. <strong>Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.</strong> Science 304: 1021-1024, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15143284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15143284</a>] [<a href="https://doi.org/10.1126/science.1096615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15143284">Liu et al. (2004)</a> concluded that their results demonstrated that distinct NMDA receptor subunits are critical factors that determine the polarity of synaptic plasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15143284" 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="#28" class="mim-tip-reference" title="Rusakov, D. A., Scimemi, A., Walker, M. C., Kullmann, D. M. <strong>Comment on 'Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.'</strong> Science 305: 1912 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448254</a>] [<a href="https://doi.org/10.1126/science.1102399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448254">Rusakov et al. (2004)</a> commented on the paper by <a href="#21" class="mim-tip-reference" title="Liu, L., Wong, T. P., Pozza, M. F., Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y. P., Wang, Y. T. <strong>Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.</strong> Science 304: 1021-1024, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15143284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15143284</a>] [<a href="https://doi.org/10.1126/science.1096615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15143284">Liu et al. (2004)</a>, suggesting that because NR2B, but not NR2A, receptors occur outside synapses and can be activated by glutamate spillover, this principle may underlie synaptic homeostasis. <a href="#35" class="mim-tip-reference" title="Wong, T. P., Liu, L., Sheng, M., Wang, Y. T. <strong>Response to comment on 'Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.'</strong> Science 305: 1912 only, 2004."None>Wong et al. (2004)</a> responded to the comments by <a href="#28" class="mim-tip-reference" title="Rusakov, D. A., Scimemi, A., Walker, M. C., Kullmann, D. M. <strong>Comment on 'Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.'</strong> Science 305: 1912 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448254</a>] [<a href="https://doi.org/10.1126/science.1102399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448254">Rusakov et al. (2004)</a> by stating that although they agreed that activation of extrasynaptic NR2B receptors by glutamate spillover may lead to heterosynaptic long-term depression, the data also supported a role of synaptic NR2B receptors in homosynaptic long-term depression. The proposed role of extrasynaptic NMDA receptor-mediated long-term depression in synaptic homeostasis may thus be temporally limited. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15448254+15143284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 304 Swiss individuals tested and genotyped, <a href="#7" class="mim-tip-reference" title="de Quervain, D. J.-F., Papassotiropoulos, A. <strong>Identification of a genetic cluster influencing memory performance and hippocampal activity in humans.</strong> Proc. Nat. Acad. Sci. 103: 4270-4274, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537520[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.0510212103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537520">de Quervain and Papassotiropoulos (2006)</a> found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (<a href="/entry/103070">103070</a>), PRKACG (<a href="/entry/176893">176893</a>), CAMK2G (<a href="/entry/602123">602123</a>), GRIN2A (<a href="/entry/138253">138253</a>), GRIN2B, GRM3 (<a href="/entry/601115">601115</a>), and PRKCA (<a href="/entry/176960">176960</a>) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. <a href="#7" class="mim-tip-reference" title="de Quervain, D. J.-F., Papassotiropoulos, A. <strong>Identification of a genetic cluster influencing memory performance and hippocampal activity in humans.</strong> Proc. Nat. Acad. Sci. 103: 4270-4274, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537520[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.0510212103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16537520">De Quervain and Papassotiropoulos (2006)</a> concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16537520" 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>Administration of the glutamate NMDA receptor agonist ketamine results in a rapid antidepressant response in treatment-resistant depressed patients. <a href="#20" class="mim-tip-reference" title="Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., Duman, R. S. <strong>mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.</strong> Science 329: 959-964, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724638</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724638[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1190287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724638">Li et al. (2010)</a> showed that ketamine rapidly activated the mTOR pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. However, ketamine is a psychomimetic drug with potential for abuse, and a more selective agent would be desirable for clinical antidepressant use. <a href="#20" class="mim-tip-reference" title="Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., Duman, R. S. <strong>mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.</strong> Science 329: 959-964, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724638</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724638[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1190287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724638">Li et al. (2010)</a> demonstrated that another compound, Ro25-6981, which selectively acts on NR2B, had similar effects to ketamine, suggesting that this effect is mediated through NMDA receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20724638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P., Kavalali, E. T., Monteggia, L. M. <strong>NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.</strong> Nature 475: 91-95, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21677641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21677641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21677641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21677641">Autry et al. (2011)</a> showed that ketamine and other NMDAR antagonists produce fast-acting behavioral antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of BDNF (<a href="/entry/113505">113505</a>). They found that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor-2 kinase (EEF2K; <a href="/entry/606968">606968</a>), resulting in reduced EEF2 phosphorylation and desuppression of translation of BDNF. Furthermore, <a href="#2" class="mim-tip-reference" title="Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P., Kavalali, E. T., Monteggia, L. M. <strong>NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.</strong> Nature 475: 91-95, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21677641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21677641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21677641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21677641">Autry et al. (2011)</a> found that inhibitors of EEF2K induce fast-acting behavioral antidepressant-like effects. <a href="#2" class="mim-tip-reference" title="Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P., Kavalali, E. T., Monteggia, L. M. <strong>NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.</strong> Nature 475: 91-95, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21677641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21677641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21677641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21677641">Autry et al. (2011)</a> concluded that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21677641" 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 rodent cerebral cortex, there is a developmental switch from Nr2b- to Nr2a-containing NMDA receptors that is driven by activity and sensory experience. This subunit switch alters NMDA receptor function and influences synaptic plasticity. Using whole-cell patch-clamp recordings from CA1 pyramidal neurons of neonatal rats and Glur5 (GRIK1; <a href="/entry/138245">138245</a>)-knockout mice, <a href="#25" class="mim-tip-reference" title="Matta, J. A., Ashby, M. C., Sanz-Clemente, A., Roche, K. W., Isaac, J. T. R. <strong>mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch.</strong> Neuron 70: 339-351, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21521618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21521618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21521618[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.neuron.2011.02.045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21521618">Matta et al. (2011)</a> found that the Nr2b-to-Nr2a switch was rapid and required Glur5 in addition to NMDA receptor activation. Glutamate binding to Glur5 led to activation of PLC (see <a href="/entry/607120">607120</a>), followed by release of calcium from intracellular stores and activation of PKC by diacylglycerol. A similar Nr2b-to-Nr2a switch requiring Glur5 occurred following visual stimulation at inputs onto layer 2/3 pyramidal neurons in mouse primary visual cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21521618" 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="#36" class="mim-tip-reference" title="Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H. <strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong> Science 370: eaay3302, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>] [<a href="https://doi.org/10.1126/science.aay3302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33033186">Yan et al. (2020)</a> found that the NMDAR subunits Grin2a and Grin2b formed a complex with Trpm4 (<a href="/entry/606936">606936</a>) in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that <a href="#36" class="mim-tip-reference" title="Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H. <strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong> Science 370: eaay3302, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>] [<a href="https://doi.org/10.1126/science.aay3302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33033186">Yan et al. (2020)</a> identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33033186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Gielen, M., Retchless, B. S., Mony, L., Johnson, J. W., Paoletti, P. <strong>Mechanism of differential control of NMDA receptor activity by NR2 subunits.</strong> Nature 459: 703-707, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19404260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19404260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19404260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19404260">Gielen et al. (2009)</a> showed that the subunit-specific gating of NMDA receptors (NMDARs) is controlled by the region formed by the NR2 N-terminal domain (NTD), an extracellular clamshell-like domain that binds allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR maximum open probability (P-O) largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2 NTD. This NTD-driven gating control also affects pharmacologic properties by setting the sensitivity to the endogenous inhibitors zinc and protons. <a href="#12" class="mim-tip-reference" title="Gielen, M., Retchless, B. S., Mony, L., Johnson, J. W., Paoletti, P. <strong>Mechanism of differential control of NMDA receptor activity by NR2 subunits.</strong> Nature 459: 703-707, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19404260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19404260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19404260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19404260">Gielen et al. (2009)</a> concluded that their results provided a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2 NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19404260" 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="#16" class="mim-tip-reference" title="Karakas, E., Simorowski, N., Furukawa, H. <strong>Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.</strong> Nature 475: 249-253, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21677647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21677647</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21677647[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21677647">Karakas et al. (2011)</a> reported that the GluN1 (GRIN1; <a href="/entry/138249">138249</a>) and GluN2B amino-terminal domains forms a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluNB2, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b amino-terminal domain from Xenopus laevis and the GluN2B amino-terminal domain from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B amino-terminal domain, by engineering of an intersubunit disulfide bond, markedly decreased sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B amino-terminal domain is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. <a href="#16" class="mim-tip-reference" title="Karakas, E., Simorowski, N., Furukawa, H. <strong>Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.</strong> Nature 475: 249-253, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21677647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21677647</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21677647[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21677647">Karakas et al. (2011)</a> concluded that their findings paved the way for improving the design of subtype-specific compounds with therapeutic value for neurologic disorders and diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21677647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Lu, W., Du, J., Goehring, A., Gouaux, E. <strong>Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation.</strong> Science 355: eaal3729, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28232581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28232581</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28232581[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aal3729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28232581">Lu et al. (2017)</a> reported structures of the triheteromeric GluN1 (GRIN1)/GluN2A (GRIN2A; <a href="/entry/138253">138253</a>)/GluN2B (GRIN2B) receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt 'closed' and 'open' clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. <a href="#22" class="mim-tip-reference" title="Lu, W., Du, J., Goehring, A., Gouaux, E. <strong>Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation.</strong> Science 355: eaal3729, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28232581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28232581</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28232581[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aal3729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28232581">Lu et al. (2017)</a> concluded that the triheteromeric NMDAR structures provided the first view of the most common NMDA receptor assembly and showed how incorporation of 2 different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28232581" 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>Intellectual Developmental Disorder, Autosomal Dominant 6, with or without Seizures</em></strong></p><p>
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In 4 of 468 patients with impaired intellectual development (MRD6; <a href="/entry/613970">613970</a>), <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> identified 4 different de novo heterozygous mutations in the GRIN2B gene (<a href="#0001">138252.0001</a>-<a href="#0004">138252.0004</a>). All 4 patients had nonspecific behavioral abnormalities, and none had seizures. <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> noted that the composition of NMDA receptors undergoes a developmental change from heterotetramers containing predominantly GRIN2B at the early stages of development to those containing GRIN2B, GRIN2A, or both subunits at a mature stage. The finding of mutations in the GRIN2B gene in patients with mental retardation suggests that the number and composition of synaptic NMDA receptors is important for proper neuronal activity and development. <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> suggested that loss of function mutations may lead to abnormal subunit function and affect neuronal ion flux and electrical transmission between neurons, resulting in developmental abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By sequencing 44 candidate genes in 2,446 autism spectrum disorder probands, <a href="#26" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> identified 4 individuals with de novo mutations in the GRIN2B gene. The mutations included a frameshift, a missense, a splice site, and a nonsense mutation (<a href="#0005">138252.0005</a>-<a href="#0008">138252.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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 10.5-year-old girl with delayed psychomotor development and mild intellectual disability who developed focal dyscognitive seizures at age 9 years and 9 months, <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> identified a heterozygous de novo mutation affecting the extracellular glutamate-binding domain (R540H; <a href="#0012">138252.0012</a>). In vitro expression studies of the variant showed a gain-of-function effect. <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> noted that the <a href="#11" class="mim-tip-reference" title="Epi4K Consortium and Epilepsy Phenome/Genome Project. <strong>De novo mutations in epileptic encephalopathies.</strong> Nature 501: 217-221, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23934111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23934111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23934111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature12439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23934111">Epi4K Consortium and Epilepsy Phenome/Genome Project (2013)</a> identified a de novo heterozygous missense GRIN2B mutation (C461F) in the extracellular glutamate-binding domain in a patient with delayed development, intellectual disability, and childhood-onset epilepsy. The C461F variant was found by exome sequencing of a cohort of 264 probands with epileptic encephalopathy; functional studies of that variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24272827+23934111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 girls, aged 10 and 6 years, with severe psychomoter developmental delay without seizures, <a href="#4" class="mim-tip-reference" title="Buonuomo, P. S., Mastrogiorgio, G., Alfieri, P., Terracciano, A., Cesario, C., Rana, I., Macchiaiolo, M., Gonfiantini, M. V., Vecchio, D., Digilio, M. C., Dentici, M. L., Cumbo, F., Novelli, A., Bartuli, A. <strong>Two new cases of nonepileptic neurodevelopmental disorder due to GRIN2B variants and detailed clinical description of the behavioral phenotype.</strong> Clin. Dysmorph. 31: 74-78, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35238837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35238837</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35238837">Buonuomo et al. (2022)</a> identified de novo heterozygous variants (R847X and G689S) in the GRIN2B gene (<a href="/entry/138252">138252</a>) using exome sequencing trio analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35238837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated girls with MRD6, <a href="#9" class="mim-tip-reference" title="den Hollander, B., Veenvliet, A. R. J., Rothuizen-Lindenschot, M., van Essen, P., Peters, G., Santos-Gomez, A., Olivella, M., Altafaj, X., Brands, M. M., Jacobs, B. A. W., van Karnebeek, C. D. <strong>Evidence for effect of l-serine, a novel therapy for GRIN2B-related neurodevelopmental disorder.</strong> Molec. Genet. Metab. 138: 107523, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36758276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36758276</a>] [<a href="https://doi.org/10.1016/j.ymgme.2023.107523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36758276">den Hollander et al. (2023)</a> identified de novo heterozygous mutations in the GRIN2B gene (I751T and G820E). The mutations were identified by trio whole-exome sequencing. Expression of each mutant GRIN2B in HEK293T cells resulted in loss of function of the NAMDR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36758276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 27</em></strong></p><p>
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In 2 unrelated children with developmental and epileptic encephalopathy-27 (DEE27; <a href="/entry/616139">616139</a>), <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> identified 2 different de novo heterozygous missense mutations in the GRIN2B gene (V618G, <a href="#0010">138252.0010</a> and N615I, <a href="#0011">138252.0011</a>). The mutations were found by targeted massive parallel resequencing of 50 known DEE genes plus candidate genes in 357 patients with epilepsy, including 91 patients with epileptic encephalopathy. The patients bearing mutations thus accounted for 2.2% (2 of 91) of that phenotypic group. In vitro functional expression studies showed that both mutations occurred in the ion channel-forming reentrant loop and resulted in increased calcium permeability and a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24272827" 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 large cohort of 86 patients with MRD6 or DEE27, <a href="#27" class="mim-tip-reference" title="Platzer, K., Yuan, H., Schutz, H., Winschel, A., Chen, W., Hu, C., Kusumoto, H., O'Heyne, H., Helbig, K. L., Tang, S., Willing, M. C., Tinkle, B. T., and 63 others. <strong>GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.</strong> J. Med. Genet. 54: 460-470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28377535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28377535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28377535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-104509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28377535">Platzer et al. (2017)</a> identified de novo heterozygous missense or truncating mutations in the GRIN2B gene; multiple mutations were identified, including several recurrent mutations (e.g., G689S, G820A, and R847X). In vitro functional expression studies of some of the missense mutations showed that they resulted in altered channel function; some (e.g., S541R, V558I, and I655F) increased glutamate EC(50) values, indicating that higher concentrations of glutamate were needed to activate the receptors, consistent with a loss of function or haploinsufficiency. In contrast, other missense mutations (e.g., S810R, M818T, and A819T) increased glutamate and glycine potency, suggesting a potential gain-of-function effect with possible excitotoxicity. There was also evidence for altered response to Mg(2+) inhibition. Most, but not all, of the missense mutations clustered within or close to ligand-binding sites or transmembrane domains. There was no correlation between missense versus truncating mutations and occurrence of seizures, although there was an association between truncating mutations and mild or moderate intellectual disability (ID) versus severe ID. In vitro studies showed that the NMDAR antagonist memantine could reduce membrane hyperactivity of some of the gain-of-function mutations, but treatment of patients with memantine did not reduce seizure frequency. Combining the results of several cohorts of over 10,000 patients with neurodevelopmental disorders and/or epilepsy who underwent genetic analysis by either gene panel sequencing or whole-exome sequencing, <a href="#27" class="mim-tip-reference" title="Platzer, K., Yuan, H., Schutz, H., Winschel, A., Chen, W., Hu, C., Kusumoto, H., O'Heyne, H., Helbig, K. L., Tang, S., Willing, M. C., Tinkle, B. T., and 63 others. <strong>GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.</strong> J. Med. Genet. 54: 460-470, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28377535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28377535</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28377535[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-104509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28377535">Platzer et al. (2017)</a> estimated the frequency of GRIN2B mutations to be 0.2%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28377535" 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>Variant Function</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Swanger, S. A., Chen, W., Wells, G., Burger, P. B., Tankovic, A., Bhattacharya, S., Strong, K. L., Hu, C., Kusumoto, H., Zhang, J., Adams, D. R., Millichap, J. J., Petrovski, S., Traynelis, S. F., Yuan, H. <strong>Mechanistic insight into NMDA receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains.</strong> Am. J. Hum. Genet. 99: 1261-1280, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839871[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.2016.10.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839871">Swanger et al. (2016)</a> assessed variation across GRIN2A (<a href="/entry/138253">138253</a>) and GRIN2B domains and determined that the agonist-binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist-binding domain of GRIN2B exhibited significantly more variation intolerance than that of GRIN2A. To understand the ramifications of missense variation in the agonist-binding domain, <a href="#31" class="mim-tip-reference" title="Swanger, S. A., Chen, W., Wells, G., Burger, P. B., Tankovic, A., Bhattacharya, S., Strong, K. L., Hu, C., Kusumoto, H., Zhang, J., Adams, D. R., Millichap, J. J., Petrovski, S., Traynelis, S. F., Yuan, H. <strong>Mechanistic insight into NMDA receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains.</strong> Am. J. Hum. Genet. 99: 1261-1280, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27839871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27839871</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27839871[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.2016.10.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27839871">Swanger et al. (2016)</a> investigated the mechanisms by which 25 rare variants in the GRIN2A and GRIN2B agonist binding domains dysregulated NMDA receptor activity. When introduced into recombinant human NMDA receptors, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. The approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GRIN2A were associated with epilepsy, whereas GRIN2B variants were associated with intellectual disability with or without seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27839871" 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="#18" class="mim-tip-reference" title="Kutsuwada, T., Sakimura, K., Manabe, T., Takayama, C., Katakura, N., Kushiya, E., Natsume, R., Watanabe, M., Inoue, Y., Yagi, T., Aizawa, S., Arakawa, M., Takahashi, T., Nakamura, Y., Mori, H., Mishina, M. <strong>Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon-2 subunit mutant mice.</strong> Neuron 16: 333-344, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8789948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8789948</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80051-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8789948">Kutsuwada et al. (1996)</a> showed that targeted disruption of the mouse Nmdar2b gene caused perinatal lethality in homozygous -/- mice. By gene targeting, <a href="#30" class="mim-tip-reference" title="Sprengel, R., Suchanek, B., Amico, C., Brusa, R., Burnashev, N., Rozov, A., Hvalby, O., Jensen, V., Paulsen, O., Andersen, P., Kim, J. J., Thompson, R. F., Sun, W., Webster, L. C., Grant, S. G. N., Eilers, J., Konnerth, A., Li, J., McNamara, J. O., Seeburg, P. H. <strong>Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo.</strong> Cell 92: 279-289, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9458051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9458051</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80921-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9458051">Sprengel et al. (1998)</a> generated mutant mice expressing the Nmdar2b gene without the large intracellular C-terminal domain. These homozygous -/- mice also died perinatally. The authors concluded that the phenotypes observed appear to reflect defective intracellular signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9458051+8789948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> generated transgenic mice overexpressing the Nmdar2b gene. Nmdar2b transient expression was enriched in the cortex and hippocampus, with little expression in the thalamus, brainstem, and cerebellum. Western blot analysis indicated about twice as much NMDAR2B protein in the transgenic mice as in wildtype mice. Using single hippocampal neurons, <a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> demonstrated that transgenic neurons retained the juvenile-like single-synapse peak NMDA-current amplitude over time in culture. Using hippocampal slices prepared from 4- to 6-month-old animals, <a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> observed enhanced NMDA receptor-mediated field responses in the transgenic mice compared with wildtype animals. There were no differences in AMPA-mediated field responses. <a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> conducted various learning tasks relevant to the forebrain regions, including novel object recognition, contextual and cued fear conditioning, and spatial learning using the hidden-platform water maze, to test learning in the transgenic mice. In all 3 tests, the transgenic mice overexpressing the Nmdr2b gene performed better than wildtype animals. <a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> demonstrated that the NMDA receptor serves as a graded molecular switch for gating the age-dependent threshold for synaptic plasticity and memory formation, thus substantially validating the Hebb learning rule, which states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. On the basis of these results, <a href="#32" class="mim-tip-reference" title="Tang, Y.-P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., Tsien, J. Z. <strong>Genetic enhancement of learning and memory in mice.</strong> Nature 401: 63-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10485705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10485705</a>] [<a href="https://doi.org/10.1038/43432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10485705">Tang et al. (1999)</a> suggested that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10485705" 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 both mice and humans, <a href="#8" class="mim-tip-reference" title="DeGiorgio, L. A., Konstantinov, K. N., Lee, S. C., Hardin, J. A., Volpe, B. T., Diamond, B. <strong>A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus.</strong> Nature Med. 7: 1189-1193, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11689882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11689882</a>] [<a href="https://doi.org/10.1038/nm1101-1189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11689882">DeGiorgio et al. (2001)</a> found that a subset of antibodies against double-stranded DNA (dsDNA) found in systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) recognized portions of the extracellular domain of the NR2A and NR2B subunits, which are found in the hippocampus, amygdala, and hypothalamus. <a href="#15" class="mim-tip-reference" title="Huerta, P. T., Kowal, C., DeGiorgio, L. A., Volpe, B. T., Diamond, B. <strong>Immunity and behavior: antibodies alter emotion.</strong> Proc. Nat. Acad. Sci. 103: 678-683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16407105[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.0510055103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407105">Huerta et al. (2006)</a> showed that mice immunized to produce anti-dsDNA/anti-NR2 IgG antibodies developed damage to neurons in the amygdala after being given epinephrine to induce leaks in the blood-brain barrier. The resulting neuronal insults were noninflammatory. Mice with antibody-mediated damage in the amygdala developed behavioral changes characterized by a deficient response to fear-conditioning paradigms. <a href="#15" class="mim-tip-reference" title="Huerta, P. T., Kowal, C., DeGiorgio, L. A., Volpe, B. T., Diamond, B. <strong>Immunity and behavior: antibodies alter emotion.</strong> Proc. Nat. Acad. Sci. 103: 678-683, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16407105[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.0510055103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407105">Huerta et al. (2006)</a> postulated that when the blood-brain barrier is compromised, neurotoxic antibodies can penetrate the central nervous system and result in cognitive, emotional, and behavioral changes, as seen in neuropsychiatric lupus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11689882+16407105" 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=138252[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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<p>In a 10-year-old German boy with moderately impaired intellectual development (MRD6; <a href="/entry/613970">613970</a>), <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> identified a de novo heterozygous G-to-A transition (411+1G-A) in intron 2 of the GRIN2B gene, predicted to result in altered splicing. Aberrant GRIN2B transcripts were not detected in patient cells, suggesting nonsense-mediated mRNA decay. The mutation was not found in 360 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" 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">rs1060499526 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060499526;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=rs1060499526" 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=rs1060499526" 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 13-year-old German girl with moderately impaired intellectual development (MRD6; <a href="/entry/613970">613970</a>), <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> identified a de novo heterozygous 2-bp deletion (803delCA) in exon 4 of the GRIN2B gene, resulting in a frameshift and premature termination. The mutation was not found in 360 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</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">rs387906636 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906636;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=rs387906636" 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=rs387906636" 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=RCV000022582 OR RCV001260642 OR RCV001541943" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022582, RCV001260642, RCV001541943" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022582...</a>
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<p>In a 13-year-old German boy with moderately impaired intellectual development (MRD6; <a href="/entry/613970">613970</a>), <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> identified a de novo heterozygous 2044C-T transition in exon 10 of the GRIN2B gene, resulting in an arg682-to-cys (R682C) substitution in a highly conserved residue in the glutamate-binding NR2B ligand-binding domain. The change was predicted to destabilize the tertiary structure of the domain; however, analysis of agonist dose-response curves revealed no differences in the affinities of wildtype and R682C mutant receptors for glutamate and glycine. The mutation was not found in 1080 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</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">rs1057519612 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519612;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=rs1057519612" 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=rs1057519612" 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=RCV000022583" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022583" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022583</a>
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<p>In a 41-year-old European woman with mildly impaired intellectual development (MRD6; <a href="/entry/613970">613970</a>), <a href="#10" class="mim-tip-reference" title="Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., Milh, M., Kortum, F., Fritsch, A., Pientka, F. K., Hellenbroich, Y., Kalscheuer, V. M., and 16 others. <strong>Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.</strong> Nature Genet. 42: 1021-1026, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20890276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20890276</a>] [<a href="https://doi.org/10.1038/ng.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20890276">Endele et al. (2010)</a> identified a de novo heterozygous A-to-G transition (2360-2A-G) in intron 11 of the GRIN2B gene, predicted to result in altered splicing. Aberrant GRIN2B transcripts were not detected in patient cells, suggesting nonsense-mediated mRNA decay. The mutation was not found in 360 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20890276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
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GRIN2B, 1-BP INS, G
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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> rs398122823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122823;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/rs398122823?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=rs398122823" 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=rs398122823" 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=RCV000032861 OR RCV000493526 OR RCV001260648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032861, RCV000493526, RCV001260648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032861...</a>
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<p>In a patient with autism and a nonverbal IQ of 62 (MRD6; <a href="/entry/613970">613970</a>), <a href="#26" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> detected a de novo heterozygous insertion of 1 basepair in the GRIN2B gene resulting in frameshift and premature termination of the protein (Ser34GlnfsX25). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
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GRIN2B, CYS456TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514555 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514555;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=rs397514555" 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=rs397514555" 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=RCV000032862" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032862" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032862</a>
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<p>In a patient with autism and a nonverbal IQ of 55 (MRD6; <a href="/entry/613970">613970</a>), <a href="#26" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> detected a de novo heterozygous cys456-to-tyr (C456Y) mutation in the GRIN2B gene. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
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GRIN2B, NT2172, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122824 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122824;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=rs398122824" 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=rs398122824" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032863</a>
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<span class="mim-text-font">
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<p>In a patient with autism and a nonverbal IQ of 65 (MRD6; <a href="/entry/613970">613970</a>), <a href="#26" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> detected a de novo heterozygous splice site mutation in the GRIN2B gene, an A-to-G transition at position 2172-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
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GRIN2B, TRP559TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122825 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122825;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=rs398122825" 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=rs398122825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032864 OR RCV000627229" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032864, RCV000627229" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032864...</a>
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<span class="mim-text-font">
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<p>In a patient with autism and a nonverbal IQ of 65 (MRD6; <a href="/entry/613970">613970</a>), <a href="#26" class="mim-tip-reference" title="O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., Munson, J., Hiatt, J. B., and 14 others. <strong>Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.</strong> Science 338: 1619-1622, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160955</a>] [<a href="https://doi.org/10.1126/science.1227764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160955">O'Roak et al. (2012)</a> detected a de novo heterozygous substitution of a termination codon for trp559 (W559X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160955" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
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GRIN2B, PRO553LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514556 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514556;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=rs397514556" 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=rs397514556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000032865 OR RCV002466416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032865, RCV002466416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032865...</a>
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<p>In a patient with severe intellectual disability, hypotonia, no speech, myopia, facial dysmorphism, inguinal hernia, and dislocated hips (MRD6; <a href="/entry/613970">613970</a>), <a href="#6" class="mim-tip-reference" title="de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. <strong>Diagnostic exome sequencing in persons with severe intellectual disability.</strong> New Eng. J. Med. 367: 1921-1929, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23033978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23033978</a>] [<a href="https://doi.org/10.1056/NEJMoa1206524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23033978">de Ligt et al. (2012)</a> identified a heterozygous 1658C-T transition in the GRIN2B gene, resulting in a pro553-to-leu (P553L) substitution. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23033978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 27</strong>
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GRIN2B, VAL618GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs672601376 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601376;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=rs672601376" 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=rs672601376" 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=RCV000149503 OR RCV001172367" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149503, RCV001172367" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149503...</a>
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<span class="mim-text-font">
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<p>In a 2-year-old boy (patient 1) with developmental and epileptic encephalopathy-27 (DEE27; <a href="/entry/616139">616139</a>), <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> identified a de novo heterozygous c.1853T-G transversion in the GRIN2B gene, resulting in a val618-to-gly (V619G) substitution within the ion channel-forming reentrant loop implicated in magnesium blockade. In vitro functional expression studies showed that the NR1 (GRIN1; <a href="/entry/138249">138249</a>)/V618G heteromer showed loss of ion-channel block by extracellular magnesium and increased calcium permeability compared to wildtype, consistent with a gain of function and neuronal hyperexcitability. He had onset of seizures at 4 months of age, and was clinically diagnosed with West syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24272827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 27</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">rs672601377 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601377;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=rs672601377" 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=rs672601377" 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=RCV000149504 OR RCV001172364" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149504, RCV001172364" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149504...</a>
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<p>In a 5-year-old girl (patient 2) with DEE27 (<a href="/entry/616139">616139</a>), <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> identified a de novo heterozygous c.1844A-T transversion in the GRIN2B gene, resulting in an asn615-to-ile (N615I) substitution within the ion channel-forming reentrant loop implicated in magnesium blockade. In vitro functional expression studies showed that the NR1 (GRIN1; <a href="/entry/138249">138249</a>)/V618G (<a href="#0010">138252.0010</a>) heteromer showed loss of ion-channel block by extracellular magnesium and increased calcium permeability compared to wildtype, consistent with a gain of function and neuronal hyperexcitability. She had onset of infantile spasms at 7 weeks of age, and was clinically diagnosed with West syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24272827" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6, WITH SEIZURES</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">rs672601378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs672601378;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=rs672601378" 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=rs672601378" 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=RCV000149505 OR RCV001260644 OR RCV002293420 OR RCV002514867" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000149505, RCV001260644, RCV002293420, RCV002514867" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000149505...</a>
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<p>In a 10-year-old girl (patient 3) with autosomal dominant intellectual developmental disorder-6 with seizures (MRD6; <a href="/entry/613970">613970</a>), <a href="#19" class="mim-tip-reference" title="Lemke, J. R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R. J., James, V. M., Pepler, A., Steiner, I., Hortnagel, K., Neidhardt, J., Ruf, S., Wolff, M., Bartholdi, D., Caraballo, R., Platzer, K., Suls, A., De Jonghe, P., Biskup, S., Weckhuysen, S. <strong>GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.</strong> Ann. Neurol. 75: 147-154, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24272827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24272827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24272827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24272827">Lemke et al. (2014)</a> identified a de novo heterozygous c.1619G-A transition in the GRIN2B gene, resulting in an arg540-to-his (R540H) substitution in the glutamate-binding domain. In vitro functional expression studies showed that the mutation resulted in a decrease of magnesium block and increased calcium permeability, resulting in a gain of function via an allosteric effect. The functional consequences of this mutation were not as severe as those observed with variants causing a more severe seizure phenotype with earlier onset (V618G, <a href="#0010">138252.0010</a> and N615I, <a href="#0011">138252.0011</a>). Accordingly, the patient, who was conceived by in vitro fertilization, showed delayed psychomotor development in early childhood. At age 9 years, she developed focal dyscognitive seizures with occasional bilateral convulsive seizures and status epilepticus with postictal paresis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24272827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1126/science.1072873" target="_blank">Full Text</a>]
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Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P., Kavalali, E. T., Monteggia, L. M.
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[<a href="https://doi.org/10.1038/nature10130" target="_blank">Full Text</a>]
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Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., Schulman, H.
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<strong>Interaction with the NMDA receptor locks CaMKII in an active conformation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11459059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11459059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11459059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Buonuomo, P. S., Mastrogiorgio, G., Alfieri, P., Terracciano, A., Cesario, C., Rana, I., Macchiaiolo, M., Gonfiantini, M. V., Vecchio, D., Digilio, M. C., Dentici, M. L., Cumbo, F., Novelli, A., Bartuli, A.
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<strong>Two new cases of nonepileptic neurodevelopmental disorder due to GRIN2B variants and detailed clinical description of the behavioral phenotype.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35238837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35238837</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35238837" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M.
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[<a href="https://doi.org/10.1056/NEJMoa1206524" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16537520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16537520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16537520[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=16537520" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0510212103" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8180471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8180471</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8180471" 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/BF00292339" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1366" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2011.02.045" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1227764" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1102399" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80921-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/43432" target="_blank">Full Text</a>]
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<strong>Response to comment on 'Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.'</strong>
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Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H.
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<strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33033186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aay3302" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 04/24/2023
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Sonja A. Rasmussen - updated : 06/10/2022<br>Ada Hamosh - updated : 03/03/2021<br>Ada Hamosh - updated : 10/18/2018<br>Cassandra L. Kniffin - updated : 08/31/2017<br>Ada Hamosh - updated : 08/11/2017<br>Cassandra L. Kniffin - updated : 12/16/2014<br>Ada Hamosh - updated : 2/12/2013<br>Ada Hamosh - updated : 1/23/2013<br>Patricia A. Hartz - updated : 2/23/2012<br>Ada Hamosh - updated : 9/6/2011<br>Ada Hamosh - updated : 8/24/2011<br>Cassandra L. Kniffin - updated : 5/12/2011<br>Ada Hamosh - updated : 9/29/2010<br>Patricia A. Hartz - updated : 3/12/2010<br>Ada Hamosh - updated : 6/16/2009<br>Cassandra L. Kniffin - updated : 4/3/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Ada Hamosh - updated : 3/3/2005<br>Ada Hamosh - updated : 6/9/2004<br>Ada Hamosh - updated : 5/29/2003<br>Ada Hamosh - updated : 11/15/2002<br>Ada Hamosh - updated : 4/16/2002<br>Ada Hamosh - updated : 6/13/2001<br>Ada Hamosh - updated : 6/8/2000<br>Orest Hurko - updated : 11/4/1999<br>Ada Hamosh - updated : 9/3/1999<br>Rebekah S. Rasooly - updated : 6/13/1998<br>Stylianos E. Antonarakis - updated : 3/21/1998
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carol : 04/24/2023
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alopez : 06/10/2022<br>carol : 04/07/2022<br>alopez : 04/06/2022<br>mgross : 03/03/2021<br>alopez : 02/24/2021<br>carol : 12/04/2020<br>alopez : 10/15/2020<br>carol : 10/22/2018<br>carol : 10/19/2018<br>alopez : 10/18/2018<br>alopez : 02/22/2018<br>carol : 09/01/2017<br>carol : 08/31/2017<br>ckniffin : 08/31/2017<br>alopez : 08/11/2017<br>alopez : 12/19/2014<br>alopez : 12/19/2014<br>mcolton : 12/16/2014<br>ckniffin : 12/16/2014<br>alopez : 10/23/2013<br>carol : 9/3/2013<br>alopez : 7/24/2013<br>carol : 2/12/2013<br>alopez : 1/25/2013<br>terry : 1/23/2013<br>mgross : 3/7/2012<br>terry : 2/23/2012<br>alopez : 9/7/2011<br>alopez : 9/7/2011<br>terry : 9/6/2011<br>alopez : 8/25/2011<br>terry : 8/24/2011<br>terry : 6/2/2011<br>wwang : 5/16/2011<br>ckniffin : 5/12/2011<br>alopez : 10/5/2010<br>terry : 9/29/2010<br>mgross : 3/15/2010<br>terry : 3/12/2010<br>wwang : 6/25/2009<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>alopez : 2/5/2008<br>terry : 1/24/2008<br>wwang : 4/17/2006<br>ckniffin : 4/3/2006<br>wwang : 3/20/2006<br>ckniffin : 3/2/2006<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>terry : 2/22/2005<br>alopez : 6/9/2004<br>terry : 6/9/2004<br>alopez : 5/29/2003<br>terry : 5/29/2003<br>carol : 1/24/2003<br>terry : 11/15/2002<br>alopez : 4/30/2002<br>alopez : 4/17/2002<br>alopez : 4/17/2002<br>alopez : 4/17/2002<br>terry : 4/16/2002<br>alopez : 6/14/2001<br>alopez : 6/14/2001<br>terry : 6/13/2001<br>alopez : 6/8/2000<br>psherman : 11/9/1999<br>carol : 11/4/1999<br>alopez : 9/3/1999<br>terry : 9/3/1999<br>psherman : 9/2/1999<br>dkim : 7/24/1998<br>psherman : 6/17/1998<br>psherman : 6/13/1998<br>carol : 3/21/1998<br>carol : 10/3/1994
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<strong>*</strong> 138252
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GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2B; GRIN2B
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT EPSILON-2; NMDAR2B<br />
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NR2B
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GRIN2B</em></strong>
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<strong>
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Cytogenetic location: 12p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:13,537,337-13,982,134 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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12p13.1
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Developmental and epileptic encephalopathy 27
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<span class="mim-font">
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616139
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Autosomal dominant
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<span class="mim-font">
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3
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Intellectual developmental disorder, autosomal dominant 6, with or without seizures
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<span class="mim-font">
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613970
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated ion channel permeable to Na+, K+, and Ca(2+) and is found at excitatory synapses throughout the brain. NMDA receptors are heterotetramers composed of 2 NMDA receptor-1 (NR1, or GRIN1; 138249) subunits and 2 NR2 subunits, such as GRIN2B (summary by Matta et al., 2011). </p>
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<strong>Cloning and Expression</strong>
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<p>By screening a human fetal brain cDNA library with a rat Nmdar2b cDNA, Hess et al. (1996) isolated a cDNA encoding NMDAR2B. The sequence of the predicted 1,484-amino acid human protein is 98% and 96% identical to the sequences of the rat and mouse Nmdar2b proteins, respectively. </p>
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<strong>Gene Structure</strong>
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<p>Endele et al. (2010) noted that the GRIN2B gene contains 13 exons. </p>
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<strong>Mapping</strong>
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</h4>
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<span class="mim-text-font">
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<p>By linkage studies in recombinant inbred lines, Madarnas et al. (1994) demonstrated that the Nmdar2b gene is located on mouse chromosome 6 between Rho (180380) and Ly49 (604274) centromerically and Glb (see 230500) telomerically. Using both somatic cell hybrids and in situ hybridization, Mandich et al. (1994) localized the human NMDAR2B gene to 12p12. </p><p>Endele et al. (2010) noted that the GRIN2B gene maps to chromosome 12p13.1. </p>
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<h4>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Hess et al. (1996) showed that human NMDAR2B functioned as an NMDA receptor when coexpressed with NMDAR1 in Xenopus oocytes. </p><p>In the hippocampus and cerebral cortex, the active subunit NMDAR1 is associated with 1 of 2 regulatory epsilon subunits: NMDAR2A (GRIN2A; 138253) or NMDAR2B. Chen et al. (1999) demonstrated a 4-fold increase in mean channel open probability in embryonic kidney cells expressing NMDAR1/NMDAR2A complexes when compared to those expressing NMDAR1/NMDAR2B. They proposed that changes in the relative expression levels of NMDAR2A and NMDAR2B could regulate peak amplitude of NMDA receptor-mediated excitatory postsynaptic potentials and thus modulate the efficiency of synaptic plasticity. </p><p>Thomas et al. (1996) demonstrated specific increases in the expression of the NMDAR2B subunit following the induction of hippocampal long-term potentiation (LTP) in the dentate gyrus of rats. This increase was delayed by several days, suggesting that it may be important in the maintenance of LTP. </p><p>Experiments with vesicles containing NMDA receptor 2B showed that they are transported along microtubules by KIF17 (605037), a neuron-specific molecular motor in neuronal dendrites. Setou et al. (2000) demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10 (602414), which is a constituent of a large protein complex including Lin2 (300172), Lin7 (603380), and the NR2B subunit. Setou et al. (2000) concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis. </p><p>Bayer et al. (2001) demonstrated that regulated CAMK2 (114078) interaction with 2 sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by facilitated CAMK2 response to synaptic calcium, suppression of inhibitory autophosphorylation of CAMK2, and, most, notably, direct generation of sustained calcium/calmodulin-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of calmodulin that may reduce downregulation of NMDA receptor activity. </p><p>Hardingham et al. (2002) reported that synaptic and extrasynaptic NMDA receptors have opposite effects on CREB (123810) function, gene regulation, and neuronal survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF; 113505) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have antiapoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. </p><p>Tu et al. (2010) found that Dapk1 (600831) was responsible for ischemia-induced neuronal cell death in mice. Dapk1 coprecipitated with the NMDA receptor complex and interacted directly with the Nr2b subunit. Ischemia activated Dapk1, and activated Dapk1 serine phosphorylated Nr2b at extrasynaptic sites, leading to injurious Ca(2+) influx and apoptotic cell death. Knockdown of Dapk1 or blocking the Dapk1-Nr2b interaction protected mice against cerebral ischemic damage. </p><p>To treat stroke without blocking NMDA receptors, Aarts et al. (2002) transduced neurons with peptides that disrupted the interaction of NMDA receptors with the postsynaptic density protein PSD95 (602887). This procedure dissociated NMDA receptors from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurologic function. Aarts et al. (2002) concluded that their approach circumvents the negative consequences associated with blocking NMDA receptors and may constitute a practical stroke therapy. </p><p>Kawakami et al. (2003) reported that synaptic distribution of the NMDA receptor GluR-epsilon-2 (NR2B) subunits in the adult mouse hippocampus is asymmetric between the left and right and between the apical and basal dendrites of single neurons. These asymmetric allocations of NR2B subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. Kawakami et al. (2003) concluded that their results provided a molecular basis for the structural and functional asymmetry of the mature brain. </p><p>Using hippocampal slice preparations, Liu et al. (2004) showed that selectively blocking NMDA receptors that contain the NR2B subunit abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A (138253)-containing NMDA receptors prevented the induction of long-term potentiation without affecting long-term depression production. Liu et al. (2004) concluded that their results demonstrated that distinct NMDA receptor subunits are critical factors that determine the polarity of synaptic plasticity. </p><p>Rusakov et al. (2004) commented on the paper by Liu et al. (2004), suggesting that because NR2B, but not NR2A, receptors occur outside synapses and can be activated by glutamate spillover, this principle may underlie synaptic homeostasis. Wong et al. (2004) responded to the comments by Rusakov et al. (2004) by stating that although they agreed that activation of extrasynaptic NR2B receptors by glutamate spillover may lead to heterosynaptic long-term depression, the data also supported a role of synaptic NR2B receptors in homosynaptic long-term depression. The proposed role of extrasynaptic NMDA receptor-mediated long-term depression in synaptic homeostasis may thus be temporally limited. </p><p>Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (103070), PRKACG (176893), CAMK2G (602123), GRIN2A (138253), GRIN2B, GRM3 (601115), and PRKCA (176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function. </p><p>Administration of the glutamate NMDA receptor agonist ketamine results in a rapid antidepressant response in treatment-resistant depressed patients. Li et al. (2010) showed that ketamine rapidly activated the mTOR pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. However, ketamine is a psychomimetic drug with potential for abuse, and a more selective agent would be desirable for clinical antidepressant use. Li et al. (2010) demonstrated that another compound, Ro25-6981, which selectively acts on NR2B, had similar effects to ketamine, suggesting that this effect is mediated through NMDA receptors. </p><p>Autry et al. (2011) showed that ketamine and other NMDAR antagonists produce fast-acting behavioral antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of BDNF (113505). They found that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor-2 kinase (EEF2K; 606968), resulting in reduced EEF2 phosphorylation and desuppression of translation of BDNF. Furthermore, Autry et al. (2011) found that inhibitors of EEF2K induce fast-acting behavioral antidepressant-like effects. Autry et al. (2011) concluded that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants. </p><p>In rodent cerebral cortex, there is a developmental switch from Nr2b- to Nr2a-containing NMDA receptors that is driven by activity and sensory experience. This subunit switch alters NMDA receptor function and influences synaptic plasticity. Using whole-cell patch-clamp recordings from CA1 pyramidal neurons of neonatal rats and Glur5 (GRIK1; 138245)-knockout mice, Matta et al. (2011) found that the Nr2b-to-Nr2a switch was rapid and required Glur5 in addition to NMDA receptor activation. Glutamate binding to Glur5 led to activation of PLC (see 607120), followed by release of calcium from intracellular stores and activation of PKC by diacylglycerol. A similar Nr2b-to-Nr2a switch requiring Glur5 occurred following visual stimulation at inputs onto layer 2/3 pyramidal neurons in mouse primary visual cortex. </p><p>Yan et al. (2020) found that the NMDAR subunits Grin2a and Grin2b formed a complex with Trpm4 (606936) in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that Yan et al. (2020) identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Gielen et al. (2009) showed that the subunit-specific gating of NMDA receptors (NMDARs) is controlled by the region formed by the NR2 N-terminal domain (NTD), an extracellular clamshell-like domain that binds allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR maximum open probability (P-O) largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2 NTD. This NTD-driven gating control also affects pharmacologic properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Gielen et al. (2009) concluded that their results provided a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2 NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively. </p><p>Karakas et al. (2011) reported that the GluN1 (GRIN1; 138249) and GluN2B amino-terminal domains forms a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluNB2, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b amino-terminal domain from Xenopus laevis and the GluN2B amino-terminal domain from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B amino-terminal domain, by engineering of an intersubunit disulfide bond, markedly decreased sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B amino-terminal domain is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. Karakas et al. (2011) concluded that their findings paved the way for improving the design of subtype-specific compounds with therapeutic value for neurologic disorders and diseases. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Lu et al. (2017) reported structures of the triheteromeric GluN1 (GRIN1)/GluN2A (GRIN2A; 138253)/GluN2B (GRIN2B) receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt 'closed' and 'open' clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. Lu et al. (2017) concluded that the triheteromeric NMDAR structures provided the first view of the most common NMDA receptor assembly and showed how incorporation of 2 different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity. </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>Intellectual Developmental Disorder, Autosomal Dominant 6, with or without Seizures</em></strong></p><p>
|
|
In 4 of 468 patients with impaired intellectual development (MRD6; 613970), Endele et al. (2010) identified 4 different de novo heterozygous mutations in the GRIN2B gene (138252.0001-138252.0004). All 4 patients had nonspecific behavioral abnormalities, and none had seizures. Endele et al. (2010) noted that the composition of NMDA receptors undergoes a developmental change from heterotetramers containing predominantly GRIN2B at the early stages of development to those containing GRIN2B, GRIN2A, or both subunits at a mature stage. The finding of mutations in the GRIN2B gene in patients with mental retardation suggests that the number and composition of synaptic NMDA receptors is important for proper neuronal activity and development. Endele et al. (2010) suggested that loss of function mutations may lead to abnormal subunit function and affect neuronal ion flux and electrical transmission between neurons, resulting in developmental abnormalities. </p><p>By sequencing 44 candidate genes in 2,446 autism spectrum disorder probands, O'Roak et al. (2012) identified 4 individuals with de novo mutations in the GRIN2B gene. The mutations included a frameshift, a missense, a splice site, and a nonsense mutation (138252.0005-138252.0008). </p><p>In a 10.5-year-old girl with delayed psychomotor development and mild intellectual disability who developed focal dyscognitive seizures at age 9 years and 9 months, Lemke et al. (2014) identified a heterozygous de novo mutation affecting the extracellular glutamate-binding domain (R540H; 138252.0012). In vitro expression studies of the variant showed a gain-of-function effect. Lemke et al. (2014) noted that the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous missense GRIN2B mutation (C461F) in the extracellular glutamate-binding domain in a patient with delayed development, intellectual disability, and childhood-onset epilepsy. The C461F variant was found by exome sequencing of a cohort of 264 probands with epileptic encephalopathy; functional studies of that variant were not performed. </p><p>In 2 girls, aged 10 and 6 years, with severe psychomoter developmental delay without seizures, Buonuomo et al. (2022) identified de novo heterozygous variants (R847X and G689S) in the GRIN2B gene (138252) using exome sequencing trio analysis. </p><p>In 2 unrelated girls with MRD6, den Hollander et al. (2023) identified de novo heterozygous mutations in the GRIN2B gene (I751T and G820E). The mutations were identified by trio whole-exome sequencing. Expression of each mutant GRIN2B in HEK293T cells resulted in loss of function of the NAMDR. </p><p><strong><em>Developmental and Epileptic Encephalopathy 27</em></strong></p><p>
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|
In 2 unrelated children with developmental and epileptic encephalopathy-27 (DEE27; 616139), Lemke et al. (2014) identified 2 different de novo heterozygous missense mutations in the GRIN2B gene (V618G, 138252.0010 and N615I, 138252.0011). The mutations were found by targeted massive parallel resequencing of 50 known DEE genes plus candidate genes in 357 patients with epilepsy, including 91 patients with epileptic encephalopathy. The patients bearing mutations thus accounted for 2.2% (2 of 91) of that phenotypic group. In vitro functional expression studies showed that both mutations occurred in the ion channel-forming reentrant loop and resulted in increased calcium permeability and a gain of function. </p><p>In a large cohort of 86 patients with MRD6 or DEE27, Platzer et al. (2017) identified de novo heterozygous missense or truncating mutations in the GRIN2B gene; multiple mutations were identified, including several recurrent mutations (e.g., G689S, G820A, and R847X). In vitro functional expression studies of some of the missense mutations showed that they resulted in altered channel function; some (e.g., S541R, V558I, and I655F) increased glutamate EC(50) values, indicating that higher concentrations of glutamate were needed to activate the receptors, consistent with a loss of function or haploinsufficiency. In contrast, other missense mutations (e.g., S810R, M818T, and A819T) increased glutamate and glycine potency, suggesting a potential gain-of-function effect with possible excitotoxicity. There was also evidence for altered response to Mg(2+) inhibition. Most, but not all, of the missense mutations clustered within or close to ligand-binding sites or transmembrane domains. There was no correlation between missense versus truncating mutations and occurrence of seizures, although there was an association between truncating mutations and mild or moderate intellectual disability (ID) versus severe ID. In vitro studies showed that the NMDAR antagonist memantine could reduce membrane hyperactivity of some of the gain-of-function mutations, but treatment of patients with memantine did not reduce seizure frequency. Combining the results of several cohorts of over 10,000 patients with neurodevelopmental disorders and/or epilepsy who underwent genetic analysis by either gene panel sequencing or whole-exome sequencing, Platzer et al. (2017) estimated the frequency of GRIN2B mutations to be 0.2%. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Swanger et al. (2016) assessed variation across GRIN2A (138253) and GRIN2B domains and determined that the agonist-binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist-binding domain of GRIN2B exhibited significantly more variation intolerance than that of GRIN2A. To understand the ramifications of missense variation in the agonist-binding domain, Swanger et al. (2016) investigated the mechanisms by which 25 rare variants in the GRIN2A and GRIN2B agonist binding domains dysregulated NMDA receptor activity. When introduced into recombinant human NMDA receptors, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. The approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GRIN2A were associated with epilepsy, whereas GRIN2B variants were associated with intellectual disability with or without seizures. </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">
|
|
<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>Kutsuwada et al. (1996) showed that targeted disruption of the mouse Nmdar2b gene caused perinatal lethality in homozygous -/- mice. By gene targeting, Sprengel et al. (1998) generated mutant mice expressing the Nmdar2b gene without the large intracellular C-terminal domain. These homozygous -/- mice also died perinatally. The authors concluded that the phenotypes observed appear to reflect defective intracellular signaling. </p><p>Tang et al. (1999) generated transgenic mice overexpressing the Nmdar2b gene. Nmdar2b transient expression was enriched in the cortex and hippocampus, with little expression in the thalamus, brainstem, and cerebellum. Western blot analysis indicated about twice as much NMDAR2B protein in the transgenic mice as in wildtype mice. Using single hippocampal neurons, Tang et al. (1999) demonstrated that transgenic neurons retained the juvenile-like single-synapse peak NMDA-current amplitude over time in culture. Using hippocampal slices prepared from 4- to 6-month-old animals, Tang et al. (1999) observed enhanced NMDA receptor-mediated field responses in the transgenic mice compared with wildtype animals. There were no differences in AMPA-mediated field responses. Tang et al. (1999) conducted various learning tasks relevant to the forebrain regions, including novel object recognition, contextual and cued fear conditioning, and spatial learning using the hidden-platform water maze, to test learning in the transgenic mice. In all 3 tests, the transgenic mice overexpressing the Nmdr2b gene performed better than wildtype animals. Tang et al. (1999) demonstrated that the NMDA receptor serves as a graded molecular switch for gating the age-dependent threshold for synaptic plasticity and memory formation, thus substantially validating the Hebb learning rule, which states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. On the basis of these results, Tang et al. (1999) suggested that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible. </p><p>In both mice and humans, DeGiorgio et al. (2001) found that a subset of antibodies against double-stranded DNA (dsDNA) found in systemic lupus erythematosus (SLE; 152700) recognized portions of the extracellular domain of the NR2A and NR2B subunits, which are found in the hippocampus, amygdala, and hypothalamus. Huerta et al. (2006) showed that mice immunized to produce anti-dsDNA/anti-NR2 IgG antibodies developed damage to neurons in the amygdala after being given epinephrine to induce leaks in the blood-brain barrier. The resulting neuronal insults were noninflammatory. Mice with antibody-mediated damage in the amygdala developed behavioral changes characterized by a deficient response to fear-conditioning paradigms. Huerta et al. (2006) postulated that when the blood-brain barrier is compromised, neurotoxic antibodies can penetrate the central nervous system and result in cognitive, emotional, and behavioral changes, as seen in neuropsychiatric lupus. </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 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</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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GRIN2B, IVS2DS, G-A, +1
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<br />
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SNP: rs1057519611,
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ClinVar: RCV000022580
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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 10-year-old German boy with moderately impaired intellectual development (MRD6; 613970), Endele et al. (2010) identified a de novo heterozygous G-to-A transition (411+1G-A) in intron 2 of the GRIN2B gene, predicted to result in altered splicing. Aberrant GRIN2B transcripts were not detected in patient cells, suggesting nonsense-mediated mRNA decay. The mutation was not found in 360 control chromosomes. </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>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</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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GRIN2B, 2-BP DEL, 803CA
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<br />
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SNP: rs1060499526,
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ClinVar: RCV000022581
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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 13-year-old German girl with moderately impaired intellectual development (MRD6; 613970), Endele et al. (2010) identified a de novo heterozygous 2-bp deletion (803delCA) in exon 4 of the GRIN2B gene, resulting in a frameshift and premature termination. The mutation was not found in 360 control chromosomes. </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>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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|
<span class="mim-text-font">
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|
GRIN2B, ARG682CYS
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<br />
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|
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SNP: rs387906636,
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|
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ClinVar: RCV000022582, RCV001260642, RCV001541943
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|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old German boy with moderately impaired intellectual development (MRD6; 613970), Endele et al. (2010) identified a de novo heterozygous 2044C-T transition in exon 10 of the GRIN2B gene, resulting in an arg682-to-cys (R682C) substitution in a highly conserved residue in the glutamate-binding NR2B ligand-binding domain. The change was predicted to destabilize the tertiary structure of the domain; however, analysis of agonist dose-response curves revealed no differences in the affinities of wildtype and R682C mutant receptors for glutamate and glycine. The mutation was not found in 1080 control chromosomes. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
GRIN2B, IVS11AS, A-G, -2
|
|
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|
|
|
<br />
|
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|
|
SNP: rs1057519612,
|
|
|
|
|
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|
|
ClinVar: RCV000022583
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 41-year-old European woman with mildly impaired intellectual development (MRD6; 613970), Endele et al. (2010) identified a de novo heterozygous A-to-G transition (2360-2A-G) in intron 11 of the GRIN2B gene, predicted to result in altered splicing. Aberrant GRIN2B transcripts were not detected in patient cells, suggesting nonsense-mediated mRNA decay. The mutation was not found in 360 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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|
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2B, 1-BP INS, G
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs398122823,
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|
|
|
|
|
gnomAD: rs398122823,
|
|
|
|
|
|
ClinVar: RCV000032861, RCV000493526, RCV001260648
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autism and a nonverbal IQ of 62 (MRD6; 613970), O'Roak et al. (2012) detected a de novo heterozygous insertion of 1 basepair in the GRIN2B gene resulting in frameshift and premature termination of the protein (Ser34GlnfsX25). </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2B, CYS456TYR
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|
|
|
<br />
|
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|
|
SNP: rs397514555,
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|
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|
|
|
|
|
ClinVar: RCV000032862
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autism and a nonverbal IQ of 55 (MRD6; 613970), O'Roak et al. (2012) detected a de novo heterozygous cys456-to-tyr (C456Y) mutation in the GRIN2B gene. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2B, NT2172, A-G, -2
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|
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|
|
|
<br />
|
|
|
|
SNP: rs398122824,
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|
|
|
|
|
|
|
ClinVar: RCV000032863
|
|
|
|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autism and a nonverbal IQ of 65 (MRD6; 613970), O'Roak et al. (2012) detected a de novo heterozygous splice site mutation in the GRIN2B gene, an A-to-G transition at position 2172-2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
GRIN2B, TRP559TER
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|
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<br />
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|
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SNP: rs398122825,
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|
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ClinVar: RCV000032864, RCV000627229
|
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</span>
|
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</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with autism and a nonverbal IQ of 65 (MRD6; 613970), O'Roak et al. (2012) detected a de novo heterozygous substitution of a termination codon for trp559 (W559X). </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
GRIN2B, PRO553LEU
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|
<br />
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|
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SNP: rs397514556,
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|
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|
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ClinVar: RCV000032865, RCV002466416
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe intellectual disability, hypotonia, no speech, myopia, facial dysmorphism, inguinal hernia, and dislocated hips (MRD6; 613970), de Ligt et al. (2012) identified a heterozygous 1658C-T transition in the GRIN2B gene, resulting in a pro553-to-leu (P553L) substitution. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 27</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
|
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|
|
GRIN2B, VAL618GLY
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<br />
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|
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SNP: rs672601376,
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|
|
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|
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ClinVar: RCV000149503, RCV001172367
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 2-year-old boy (patient 1) with developmental and epileptic encephalopathy-27 (DEE27; 616139), Lemke et al. (2014) identified a de novo heterozygous c.1853T-G transversion in the GRIN2B gene, resulting in a val618-to-gly (V619G) substitution within the ion channel-forming reentrant loop implicated in magnesium blockade. In vitro functional expression studies showed that the NR1 (GRIN1; 138249)/V618G heteromer showed loss of ion-channel block by extracellular magnesium and increased calcium permeability compared to wildtype, consistent with a gain of function and neuronal hyperexcitability. He had onset of seizures at 4 months of age, and was clinically diagnosed with West syndrome. </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>.0011 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 27</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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GRIN2B, ASN615ILE
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<br />
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SNP: rs672601377,
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ClinVar: RCV000149504, RCV001172364
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a 5-year-old girl (patient 2) with DEE27 (616139), Lemke et al. (2014) identified a de novo heterozygous c.1844A-T transversion in the GRIN2B gene, resulting in an asn615-to-ile (N615I) substitution within the ion channel-forming reentrant loop implicated in magnesium blockade. In vitro functional expression studies showed that the NR1 (GRIN1; 138249)/V618G (138252.0010) heteromer showed loss of ion-channel block by extracellular magnesium and increased calcium permeability compared to wildtype, consistent with a gain of function and neuronal hyperexcitability. She had onset of infantile spasms at 7 weeks of age, and was clinically diagnosed with West syndrome. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6, WITH SEIZURES</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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GRIN2B, ARG540HIS
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<br />
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SNP: rs672601378,
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ClinVar: RCV000149505, RCV001260644, RCV002293420, RCV002514867
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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 (patient 3) with autosomal dominant intellectual developmental disorder-6 with seizures (MRD6; 613970), Lemke et al. (2014) identified a de novo heterozygous c.1619G-A transition in the GRIN2B gene, resulting in an arg540-to-his (R540H) substitution in the glutamate-binding domain. In vitro functional expression studies showed that the mutation resulted in a decrease of magnesium block and increased calcium permeability, resulting in a gain of function via an allosteric effect. The functional consequences of this mutation were not as severe as those observed with variants causing a more severe seizure phenotype with earlier onset (V618G, 138252.0010 and N615I, 138252.0011). Accordingly, the patient, who was conceived by in vitro fertilization, showed delayed psychomotor development in early childhood. At age 9 years, she developed focal dyscognitive seizures with occasional bilateral convulsive seizures and status epilepticus with postictal paresis. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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