4979 lines
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- *138253 - GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2A; GRIN2A
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<p>
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<span class="h4">*138253</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<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="#cytogenetics">Cytogenetics</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="#evolution">Evolution</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/138253">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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<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=ENSG00000183454;t=ENST00000330684" 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=2903" 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=138253" 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=ENSG00000183454;t=ENST00000330684" 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_000833,NM_001134407,NM_001134408,XM_017023172,XM_017023173,XM_047433993,XM_047433994" 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_001134407" 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=138253" 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=00698&isoform_id=00698_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/GRIN2A" 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/558749,1899200,4504125,14285603,62088970,109658650,119605593,194380692,197313636,197313638,219519943,1034594391,1034594393,1979593025,2217305645,2217305648,2462548646,2462548648,2462548650,2462548652" 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/Q12879" 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=2903" 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=ENSG00000183454;t=ENST00000330684" 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=GRIN2A" 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=GRIN2A" 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+2903" 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/GRIN2A" 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:2903" 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/2903" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000330684.4&hgg_start=9753404&hgg_end=10182908&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:4585" 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:4585" 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/grin2a" 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=138253[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=138253[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/GRIN2A/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/ENSG00000183454" 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=GRIN2A" 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=GRIN2A" 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=GRIN2A" 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=GRIN2A&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/PA28979" 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:4585" 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:95820" 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/GRIN2A#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:95820" 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/2903/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=2903" 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-070424-129" 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:2903" 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=GRIN2A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 230438007<br />
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<strong>ICD10CM:</strong> G40.8<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
138253
|
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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>
|
|
<span class="mim-font">
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GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2A; GRIN2A
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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>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT EPSILON-1; NMDAR2A<br />
|
|
NR2A
|
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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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GRIN2A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRIN2A</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/182?start=-3&limit=10&highlight=182">16p13.2</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:9753404-10182908&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:9,753,404-10,182,908</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/182?start=-3&limit=10&highlight=182">
|
|
16p13.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Epilepsy, focal, with speech disorder and with or without impaired intellectual development
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/245570"> 245570 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
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</tr>
|
|
|
|
|
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</tbody>
|
|
</table>
|
|
</div>
|
|
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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 GRIN2A (summary by <a href="#19" 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><a href="#30" class="mim-tip-reference" title="Takano, H., Onodera, O., Tanaka, H., Mori, H., Sakimura, K., Hori, T., Kobayashi, H., Mishina, M., Tsuji, S. <strong>Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel.</strong> Biochem. Biophys. Res. Commun. 197: 922-926, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8267632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8267632</a>] [<a href="https://doi.org/10.1006/bbrc.1993.2567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8267632">Takano et al. (1993)</a> had previously shown by molecular cloning and expression of cDNAs that the epsilon and zeta subfamilies of the mouse glutamate receptor channel subunits constitute NMDA receptor channels. The 4 members of the mouse epsilon subfamily, the E1, E2 (GRIN2B; <a href="/entry/138252">138252</a>), E3 (GRIN2C; <a href="/entry/138254">138254</a>), and E4 (GRIN2D; <a href="/entry/602717">602717</a>) subunits, are distinct in distribution, functional properties, and regulation. Rat counterparts of the mouse E1, E2, E3, E4, and zeta-1 (Z1, or GRIN1) subunits had also been isolated and designated Nr2a, Nr2b, Nr2c, Nr2d, and Nmdar1, respectively (<a href="#21" class="mim-tip-reference" title="Monyer, H., Sprengel, R., Schoepfer, R., Herb, A., Higuchi, M., Lomeli, H., Burnashev, N., Sakmann, B., Seeburg, P. H. <strong>Heteromeric NMDA receptors: molecular and functional distinction of subtypes.</strong> Science 256: 1217-1221, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1350383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1350383</a>] [<a href="https://doi.org/10.1126/science.256.5060.1217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1350383">Monyer et al., 1992</a>; <a href="#12" class="mim-tip-reference" title="Ishii, T., Moriyoshi, K., Sugihara, H., Sakurada, K., Kadotani, H., Yokoi, M., Akazawa, C., Shigemoto, R., Mizuno, N., Masu, M., Nakanishi, S. <strong>Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits.</strong> J. Biol. Chem. 268: 2836-2843, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8428958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8428958</a>]" pmid="8428958">Ishii et al., 1993</a>). <a href="#30" class="mim-tip-reference" title="Takano, H., Onodera, O., Tanaka, H., Mori, H., Sakimura, K., Hori, T., Kobayashi, H., Mishina, M., Tsuji, S. <strong>Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel.</strong> Biochem. Biophys. Res. Commun. 197: 922-926, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8267632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8267632</a>] [<a href="https://doi.org/10.1006/bbrc.1993.2567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8267632">Takano et al. (1993)</a> reported the molecular cloning of partial cDNA and genomic DNA clones encoding human NMDA receptor channel subunits. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1350383+8267632+8428958" 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 screening a human cerebellar cDNA library with a partial NMDAR2A cDNA generated by PCR using rat NMDAR2 sequences, <a href="#10" 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> cloned a full-length NMDAR2A cDNA. The predicted protein contains 1,464-amino acids. <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="#6" 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 GRIN2A gene contains 14 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 fluorescence in situ hybridization, <a href="#30" class="mim-tip-reference" title="Takano, H., Onodera, O., Tanaka, H., Mori, H., Sakimura, K., Hori, T., Kobayashi, H., Mishina, M., Tsuji, S. <strong>Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel.</strong> Biochem. Biophys. Res. Commun. 197: 922-926, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8267632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8267632</a>] [<a href="https://doi.org/10.1006/bbrc.1993.2567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8267632">Takano et al. (1993)</a> mapped the genes for the E1 subunit to 16p13, the E3 subunit to 17q25, and the Z1 subunit to 9q34. <a href="#13" class="mim-tip-reference" title="Kalsi, G., Whiting, P., Le Bourdelles, B., Callen, D., Barnard, E. A., Gurling, H. <strong>Localization of the human NMDAR2D receptor subunit gene (GRIN2D) to 19q13.1-qter, the NMDAR2A subunit gene to 16p13.2 (GRIN2A), and the NMDAR2C subunit gene (GRIN2C) to 17q24-q25 using somatic cell hybrid and radiation hybrid mapping panels.</strong> Genomics 47: 423-425, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9480759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9480759</a>] [<a href="https://doi.org/10.1006/geno.1997.5132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9480759">Kalsi et al. (1998)</a> refined the localization of the GRIN2A gene to 16p13.2 by PCR of a regional somatic cell hybrid mapping panel for chromosome 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8267632+9480759" 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="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> found that human NMDAR2A 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><a href="#9" 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="#14" class="mim-tip-reference" title="Lee, F. J. S., Xue, S., Pei, L., Vukusic, B., Chery, N., Wang, Y., Wang, Y. T., Niznik, H. B., Yu, X., Liu, F. <strong>Dual recognition of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor.</strong> Cell 111: 219-230, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12408866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12408866</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00962-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12408866">Lee et al. (2002)</a> reported that dopamine D1 receptors (<a href="/entry/126449">126449</a>) modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A and NR2A. While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see <a href="/entry/171833">171833</a>)-dependent pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12408866" 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="#31" class="mim-tip-reference" title="Wang, J., Liu, S., Fu, Y., Wang, J. H., Lu, Y. <strong>Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.</strong> Nature Neurosci. 6: 1039-1047, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14502288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14502288</a>] [<a href="https://doi.org/10.1038/nn1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14502288">Wang et al. (2003)</a> showed that transient forebrain ischemia in rat caused hippocampal CA1 pyramidal neuron cell death. Ischemia in these cells led to an increase in p25, the truncated and deleterious form of the neuron-specific activator p35 (<a href="/entry/603460">603460</a>), which was associated with prolonged activation of cyclin-dependent kinase-5 (CDK5; <a href="/entry/123831">123831</a>). Activated CDK5 phosphorylated the NMDA receptor-2A subunit at ser1232, resulting in enhanced current activity through NMDA synaptic receptors. Inhibition of CDK5 or of the interaction between CDK5 and NR2A protected CA1 pyramidal cells from ischemic insult. <a href="#31" class="mim-tip-reference" title="Wang, J., Liu, S., Fu, Y., Wang, J. H., Lu, Y. <strong>Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.</strong> Nature Neurosci. 6: 1039-1047, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14502288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14502288</a>] [<a href="https://doi.org/10.1038/nn1119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14502288">Wang et al. (2003)</a> concluded that modulation of NMDA receptors by CDK5 is the primary intracellular event underlying ischemic injury of CA1 pyramidal neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14502288" 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="#17" 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 (<a href="/entry/138252">138252</a>) abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A-containing NMDA receptors prevented the induction of long-term potentiation without affecting long-term depression production. <a href="#17" 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="#25" 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="#17" 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="#33" 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="#25" 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>By examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, <a href="#22" class="mim-tip-reference" title="Popescu, G., Robert, A., Howe, J. R., Auerbach, A. <strong>Reaction mechanism determines NMDA receptor response to repetitive stimulation.</strong> Nature 430: 790-793, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15306812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15306812</a>] [<a href="https://doi.org/10.1038/nature02775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15306812">Popescu et al. (2004)</a> showed that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predicted that, after binding neurotransmitter, receptors hesitate for approximately 4 milliseconds in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initial fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on the pulse frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15306812" 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="#3" 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, 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="#3" 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><a href="#20" class="mim-tip-reference" title="Micu, I., Jiang, Q., Coderre, E., Ridsdale, A., Zhang, L., Woulfe, J., Yin, X., Trapp, B. D., McRory, J. E., Rehak, R., Zamponi, G. W., Wang, W., Stys, P. K. <strong>NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.</strong> Nature 439: 988-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16372019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372019</a>] [<a href="https://doi.org/10.1038/nature04474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16372019">Micu et al. (2006)</a> showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists, but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. <a href="#20" class="mim-tip-reference" title="Micu, I., Jiang, Q., Coderre, E., Ridsdale, A., Zhang, L., Woulfe, J., Yin, X., Trapp, B. D., McRory, J. E., Rehak, R., Zamponi, G. W., Wang, W., Stys, P. K. <strong>NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.</strong> Nature 439: 988-992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16372019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372019</a>] [<a href="https://doi.org/10.1038/nature04474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16372019">Micu et al. (2006)</a> concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16372019" 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="#19" 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="#34" 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="#34" 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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<a href="#7" class="mim-tip-reference" title="Furukawa, H., Singh, S. K., Mancusso, R., Gouaux, E. <strong>Subunit arrangement and function in NMDA receptors.</strong> Nature 438: 185-192, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16281028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16281028</a>] [<a href="https://doi.org/10.1038/nature04089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16281028">Furukawa et al. (2005)</a> reported the crystal structure of the ligand-binding core of NR2A with glutamate and that of the NR1 (GRIN1; <a href="/entry/138249">138249</a>)-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defined the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiologic experiments, confirmed that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyr535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16281028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Gielen, M., Siegler Retchless, B., 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="#8" class="mim-tip-reference" title="Gielen, M., Siegler Retchless, B., 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><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#18" 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)/GluN2B (GRIN2B; <a href="/entry/138252">138252</a>) 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="#18" 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><a href="#23" class="mim-tip-reference" title="Reutlinger, C., Helbig, I., Gawelczyk, B., Subero, J. I. M., Tonnies, H., Muhle, H., Finsterwalder, K., Vermeer, S., Pfundt, R., Sperner, J., Stefanova, I., Gillessen-Kaesbach, G., von Spiczak, S., van Baalen, A., Boor, R., Siebert, R., Stephani, U., Caliebe, A. <strong>Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region.</strong> Epilepsia 51: 1870-1873, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20384727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20384727</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2010.02555.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20384727">Reutlinger et al. (2010)</a> reported 3 unrelated patients with different deletions of chromosome 16p13 including the GRIN2A gene who had early-onset focal epilepsy, severe intellectual disability, and lack of speech or delayed speech development (<a href="/entry/245570">245570</a>). EEG available from 2 patients showed centrotemporal spikes, reminiscent of Rolandic epilepsy, and electrical status epilepticus in sleep (ESES). All showed delayed global development from birth or early infancy. All had variable dysmorphic features, including low-set ears, epicanthal folds, hypertelorism, deep-set eyes, broad nasal tip, short nose, and brachydactyly. Genomewide screening for structural genomic variants identified 3 different deletions, ranging in size from 980 kb to 2.6 Mb, in the 3 patients. Two of the deletions were confirmed to be de novo; parental samples from the third patient were unavailable. The only gene located in the critical shared region of all 3 patients was GRIN2A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20384727" 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>Focal Epilepsy and Speech Disorder with or without Mental Retardation</em></strong></p><p>
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Heterozygous germline mutations in the GRIN2A gene have been found in focal epilepsy with speech disorder (FESD; <a href="/entry/245570">245570</a>), a childhood-onset seizure disorder with a highly variable phenotype. FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by <a href="#16" class="mim-tip-reference" title="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al., 2013</a>; <a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al., 2013</a>; <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. <strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong> Nature Genet. 45: 1073-1076, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23933818[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/ng.2727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933818">Carvill et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23933820+23933818+23933819" 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 3 members of a German family with childhood onset of focal seizures associated with variable learning difficulties and mental retardation (<a href="/entry/245570">245570</a>), <a href="#6" 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 heterozygous mutation in the GRIN2A gene (Q218X; <a href="#0001">138253.0001</a>). Another heterozygous de novo mutation (N615K; <a href="#0002">138253.0002</a>) was found in a 3-year-old French girl with severe mental retardation and early-onset epileptic spasms and myoclonic seizures. The 2 mutations had a frequency of 1 in 254 alleles from 127 patients with a history of epilepsy and/or abnormal EEG and variable degrees of mental retardation. These findings suggested that the GRIN2A gene is important for proper neuronal activity and development. <a href="#6" 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 GRIN2A 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 sequence analysis of the GRIN2A gene in 519 probands with a range of epileptic encephalopathies, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. <strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong> Nature Genet. 45: 1073-1076, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23933818[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/ng.2727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933818">Carvill et al. (2013)</a> identified heterozygous mutations (<a href="#0005">138253.0005</a>-<a href="#0007">138253.0007</a>) in 4 probands, all of whom came from the cohort of 44 patients with epilepsy-aphasia syndromes (9% of probands with epilepsy-aphasia syndromes). One of the probands was from the family reported by <a href="#27" class="mim-tip-reference" title="Scheffer, I. E., Jones, L., Pozzebon, M., Howell, R. A., Saling, M. M., Berkovic, S. F. <strong>Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation.</strong> Ann. Neurol. 38: 633-642, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7574460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7574460</a>] [<a href="https://doi.org/10.1002/ana.410380412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7574460">Scheffer et al. (1995)</a> with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia; a heterozygous splice site mutation (<a href="#0005">138253.0005</a>) segregated with the disorder in all 7 patients in this family. Two affected members of an unrelated family with epileptic encephalopathy with continuous spike and wave in slow-wave sleep (CSWS) also carried this mutation. Both were Australian families of European descent, and haplotype analysis indicated a founder effect. Three sibs from another family with CSWS or intermediate epilepsy-aphasia disorder carried a different heterozygous mutation (<a href="#0007">138253.0007</a>). The fourth family with a GRIN2A mutation was diagnosed with Landau-Kleffner syndrome (LKS). The findings indicated that GRIN2A mutations can be associated with a wide range of epilepsy-aphasia spectrum phenotypes. No GRIN2A mutations were found in 475 patients with other epileptic encephalopathy phenotypes or in 81 patients with benign epilepsy with centrotemporal spikes (BECTS). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23933818+7574460" 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="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al. (2013)</a> examined the role of the GRIN2A gene in 66 probands with LKS or CSWS. Heterozygous inherited or de novo mutations (see, e.g., <a href="#0008">138253.0008</a>-<a href="#0010">138253.0010</a>) were found in 7 of 7 families and in 6 of 59 patients with sporadic disease. Segregation studies in the families showed that some mutation carriers had atypical rolandic epilepsy. Two mutation carriers reportedly had benign childhood epilepsy. Most mutation carriers had dysphasia or verbal dyspraxia. Some mutation carriers were unaffected, indicating incomplete penetrance. Heterozygous GRIN2A mutations were subsequently found in 2 families with atypical rolandic epilepsy. One family with a mutation in the SRPX2 gene (<a href="/entry/300642#0001">300642.0001</a>; <a href="#24" class="mim-tip-reference" title="Roll, P., Rudolf, G., Pereira, S., Royer, B., Scheffer, I. E., Massacrier, A., Valenti, M.-P., Roeckel-Trevisiol, N., Jamali, S., Beclin, C., Seegmuller, C.., Metz-Lutz, M.-N. <strong>{and 18 others}: SRPX2 mutations in disorders of language cortex and cognition.</strong> Hum. Molec. Genet. 15: 1195-1207, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16497722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16497722</a>] [<a href="https://doi.org/10.1093/hmg/ddl035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16497722">Roll et al., 2006</a>; <a href="/entry/300643">300643</a>) also carried a heterozygous GRIN2A mutation. In total, 14 point mutations and 2 small deletions involving the GRIN2A gene (15 kb and 75 kb, respectively) were identified. Functional studies showed that 2 of the missense mutations caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. GRIN2A mutations were located in different domains of the protein, and there were no apparent genotype/phenotype correlations. <a href="#16" class="mim-tip-reference" title="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al. (2013)</a> concluded that GRIN2A mutations represent a major genetic determinant of LKS and CSWS, as well as related epileptic disorders in the same clinical continuum, such as atypical rolandic epilepsy and speech impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23933820+16497722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al. (2013)</a> identified heterozygous mutations in the GRIN2A gene (see, e.g., <a href="#0005">138253.0005</a>; <a href="#0011">138253.0011</a>-<a href="#0012">138253.0012</a>) in 27 (7.5%) of 359 patients from 2 independent cohorts with idiopathic focal epilepsy syndromes, including Landau-Kleffner syndrome, CSWS, atypical rolandic epilepsy, and benign epilepsy of childhood with centrotemporal spikes. Mutations occurred at a significantly higher frequency in patients compared to the Exome Variant Server (0.6%; p = 4.83 x 10(-18)) or in controls of European ancestry (p = 1.18 x 10(-16)). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12 (4.9%) of 245 individuals with BECTS to 9 (17.6%) of 51 with LKS/CSWS. Splice site, truncating, and frameshift mutations were more commonly associated with the more severe phenotypes, and missense mutations were more commonly associated with the more benign phenotypes. Segregation status was available for 18 families. The mutations segregated with a phenotype of different epileptic disorders within the families, ranging from BECTS to learning disabilities and intellectual disability to atypical rolandic epilepsy and CSWS; some mutations carriers were unaffected. Exon-disrupting microdeletions of the GRIN2A gene were also found in 3 (1%) of 286 individuals screened for copy number variations. The findings indicated that alterations of the GRIN2A gene are a major genetic risk factor for various types of idiopathic focal epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933819" 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="#29" 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 and GRIN2B (<a href="/entry/138252">138252</a>) 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="#29" 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 nonsynaptic 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><p><strong><em>Somatic Mutations in Melanoma</em></strong></p><p>
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Using exome sequencing, <a href="#32" class="mim-tip-reference" title="Wei, X., Walia, V., Lin, J. C., Teer, J. K., Prickett, T. D., Gartner, J., Davis, S., NISC Comparative Sequencing Program, Stemke-Hale, K., Davies, M. A., Gershenwald, J. E., Robinson, W., Robinson, S., Rosenberg, S. A., Samuels, Y. <strong>Exome sequencing identifies GRIN2A as frequently mutated in melanoma.</strong> Nature Genet. 43: 442-446, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21499247[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/ng.810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21499247">Wei et al. (2011)</a> found somatic mutations in the GRIN2A gene in 6 of 14 melanoma (<a href="/entry/155600">155600</a>) samples. A further 11 somatic mutations were found in a prevalence screen of 38 additional melanomas, and the findings were validated in 2 more panel sets. Overall, there were 34 distinct GRIN2A mutations in 135 melanoma samples (25.2%). These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21499247" 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>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, <a href="#5" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including GRIN2A, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. <a href="#5" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15620360" 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="#26" class="mim-tip-reference" title="Sakimura, K., Kutsuwada, T., Ito, I., Manabe, T., Takayama, C., Kushiya, E., Yagi, T., Aizawa, S., Inoue, Y., Sugiyama, H., Mishina, M. <strong>Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit.</strong> Nature 373: 151-155, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7816096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7816096</a>] [<a href="https://doi.org/10.1038/373151a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7816096">Sakimura et al. (1995)</a> showed that targeted disruption of the mouse Nmdar2a gene produced mice that were viable, although impaired hippocampal plasticity was observed in homozygous -/- mice. By gene targeting, <a href="#28" 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 Nmdar2a gene without the large intracellular C-terminal domain. These mice were viable but exhibited impaired synaptic plasticity and contextual memory. The authors concluded that the observed phenotypes appear to reflect defective intracellular signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9458051+7816096" 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="#4" 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="#11" 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-N2R 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="#11" 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=16407105+11689882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 members of a German family with childhood seizures and variable neurodevelopmental defects ranging from mental retardation to learning difficulties (FESD; <a href="/entry/245570">245570</a>), <a href="#6" 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 heterozygous 652C-T transition in exon 4 of the GRIN2A gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation was not found in 360 control chromosomes, and the mutant transcript was degraded by nonsense-mediated mRNA decay. These findings indicated loss of function. <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>In a 3-year-old French girl early-onset epileptic spasms and myoclonic seizures and severe mental retardation (FESD; <a href="/entry/245570">245570</a>), <a href="#6" 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 1845C-A transversion in exon 10 of the GRIN2A gene, resulting in an asn615-to-lys (N615K) substitution in a conserved residue of the membrane reentrant loop (P-loop). The mutation was not found in 1,080 control chromosomes. In vitro functional expression studies showed that the mutant receptor had decreased calcium permeability. Moreover, coexpression with the wildtype protein showed a dominant-negative effect. <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 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397514557 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514557;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=rs397514557" 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=rs397514557" 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=RCV000032866" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032866" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032866</a>
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<p>In a patient with severe intellectual disability, dysplastic corpus callosum, myelination delay, epilepsy, severe feeding problems, hypothyroidism, and mild facial dysmorphism (FESD; <a href="/entry/245570">245570</a>), <a href="#2" 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 de novo heterozygous 1945C-G transversion in the GRIN2A gene, resulting in a leu649-to-val (L649V) substitution. Functional studies 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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<strong>.0004 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397518450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518450;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=rs397518450" 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=rs397518450" 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=RCV000032867 OR RCV001091973 OR RCV004629145" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032867, RCV001091973, RCV004629145" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032867...</a>
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<p>In a patient with severe intellectual disability, no speech, epilepsy since 9 months of age, and spasticity (FESD; <a href="/entry/245570">245570</a>), <a href="#2" 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 de novo heterozygous 1655C-G transversion in the GRIN2A gene, resulting in a pro522-to-arg (P522R) substitution. Functional studies 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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<strong>.0005 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397518465 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518465;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=rs397518465" 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=rs397518465" 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=RCV000074386 OR RCV000656049 OR RCV000726036 OR RCV002274908" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074386, RCV000656049, RCV000726036, RCV002274908" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074386...</a>
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<p>In affected members of a family with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (FESD; <a href="/entry/245570">245570</a>), originally reported by <a href="#27" class="mim-tip-reference" title="Scheffer, I. E., Jones, L., Pozzebon, M., Howell, R. A., Saling, M. M., Berkovic, S. F. <strong>Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation.</strong> Ann. Neurol. 38: 633-642, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7574460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7574460</a>] [<a href="https://doi.org/10.1002/ana.410380412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7574460">Scheffer et al. (1995)</a>, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. <strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong> Nature Genet. 45: 1073-1076, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23933818[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/ng.2727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933818">Carvill et al. (2013)</a> identified a heterozygous G-to-A transition in intron 4 of the GRIN2A gene (c.1007+1G-A), predicted to result in the skipping of exon 4 and premature termination (Phe139IlefsTer15). The mutation was not found in 6,500 control exomes. The same heterozygous mutation was also found in a father and son with epileptic encephalopathy with continuous spike and wave in slow-wave sleep. Analysis of patient cells showed that the mutant transcript underwent nonsense-mediate mRNA decay. Both of the families were of European descent, and haplotype analysis indicated a founder effect. The findings suggested that GRIN2A mutations can cause a spectrum of epilepsy-aphasia phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23933818+7574460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al. (2013)</a> identified a heterozygous c.1007+1G-A in 7 affected individuals from 3 unrelated families and in a singleton individual, all with variable manifestations of epilepsy, including Landau-Kleffner syndrome, continuous spike and waves during slow-wave sleep, atypical benign partial epilepsy, and benign epilepsy with centrotemporal spikes. <a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al. (2013)</a> suggested that additional modifying factors might explain the phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933819" 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 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397518466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518466;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=rs397518466" 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=rs397518466" 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=RCV000074387 OR RCV004721258" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074387, RCV004721258" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074387...</a>
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<p>In 2 sisters with focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>), with the clinical diagnosis of Landau-Kleffner syndrome, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. <strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong> Nature Genet. 45: 1073-1076, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23933818[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/ng.2727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933818">Carvill et al. (2013)</a> identified a heterozygous c.2T-C transition in the GRIN2A gene, resulting in a met1-to-thr (M1T) substitution. The mutation was predicted to have detrimental effects on protein synthesis, but RNA was not available. Their father, who had unclassified epilepsy and speech/language disorder, also carried the mutation. The mutation was not found in 6,500 control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933818" 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 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397518468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518468;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=rs397518468" 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=rs397518468" 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=RCV000074389 OR RCV001557828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074389, RCV001557828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074389...</a>
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<p>In 3 sibs with focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>), with the clinical diagnosis of epilepsy-aphasia disorder or continuous spike and waves during slow-wave sleep syndrome, <a href="#1" class="mim-tip-reference" title="Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. <strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong> Nature Genet. 45: 1073-1076, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933818/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933818</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23933818[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/ng.2727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933818">Carvill et al. (2013)</a> identified a heterozygous c.1592C-T transition in the GRIN2A gene, resulting in a thr531-to-met (T531M) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in 6,500 control exomes. Coexpression of the mutant protein with wildtype GRIN1 (<a href="/entry/138249">138249</a>) in COS-7 cells resulted in a shift in NMDA receptor kinetics, with a 4-fold increase in the mean duration of the open state compared to wildtype channels. The patients had onset between ages 6.5 and 11 years of focal dyscognitive or tonic-clonic seizures that remitted in 2 patients by age 11 years. The patients had variably delayed development, mild intellectual disability, and speech/language difficulties. EEG findings were all abnormal and differed slightly, including centrotemporal spikes, high-voltage discharges while awake, and continuous spike-waves during sleep. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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">rs397518469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518469;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=rs397518469" 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=rs397518469" 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=RCV000074390" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074390" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074390</a>
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<p>In affected members of a 3-generation family with variable expression of focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>), including clinical diagnoses of continuous spike and waves during slow-wave sleep (CSWS), Landau-Kleffner syndrome, and atypical rolandic epilepsy, <a href="#16" class="mim-tip-reference" title="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al. (2013)</a> identified a heterozygous A-to-G transition in intron 5 of the GRIN2A gene (c.1123-2A-G), resulting in the skipping of exon 5 and premature termination (Val375fsTer). One mutation carrier was unaffected, suggesting incomplete penetrance. The findings were consistent with haploinsufficiency as the pathogenic effect. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933820" 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="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
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GRIN2A, ARG518HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397518470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518470;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=rs397518470" 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=rs397518470" 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=RCV000074391 OR RCV000379543" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074391, RCV000379543" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074391...</a>
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<p>In a patient with focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, <a href="#16" class="mim-tip-reference" title="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al. (2013)</a> identified a heterozygous c.1553G-A transition in the GRIN2A gene, resulting in an arg518-to-his (R518H) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes, or Exome Variant Server databases. The mutation was also present in the patient's brother, who had atypical rolandic epilepsy with dysphasia, and the father, who had verbal dyspraxia but no seizures. Another sib of the proband, who did not carry the mutation, had centrotemporal spikes on EEG without seizures, thus representing a phenocopy. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933820" 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 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
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GRIN2A, PHE652VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397518471 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518471;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=rs397518471" 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=rs397518471" 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=RCV000074392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074392</a>
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<p>In a patient with focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>) and autistic features, with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, <a href="#16" class="mim-tip-reference" title="Lesca, G., Rudolf, G., Bruneau, N., Lozovaya, N., Labalme, A., Boutry-Kryza, N., Salmi, M., Tsintsadze, T., Addis, L., Motte, J., Wright, S., Tsintsadze, V., and 17 others. <strong>GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.</strong> Nature Genet. 45: 1061-1066, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933820</a>] [<a href="https://doi.org/10.1038/ng.2726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933820">Lesca et al. (2013)</a> identified a de novo heterozygous c.1954T-G transversion in the GRIN2A gene, resulting in a phe652-to-val (F652V) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933820" 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="0011" class="mim-anchor"></a>
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<strong>.0011 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
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GRIN2A, ARG681TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397518472 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518472;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=rs397518472" 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=rs397518472" 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=RCV000074393 OR RCV000260469" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074393, RCV000260469" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074393...</a>
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<p>In a patient with focal epilepsy and speech disorder (FESD; <a href="/entry/245570">245570</a>), with the clinical diagnosis of Landau-Kleffner syndrome, <a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al. (2013)</a> identified a heterozygous c.2941C-T transition in the GRIN2A gene, resulting in an arg681-to-ter (R681X) substitution. The patient had a learning disability and language disorder. Family history showed that 2 relatives with learning disabilities also carried the mutation, as did an unaffected individual. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933819" 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="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
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GRIN2A, TYR943TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397518467 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518467;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=rs397518467" 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=rs397518467" 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=RCV000074388" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074388" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074388</a>
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<p>In a patient with focal epilepsy and speech disorder with mental retardation (FESD; <a href="/entry/245570">245570</a>), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, <a href="#15" class="mim-tip-reference" title="Lemke, J. R., Lal, D., Reinthaler, E. M., Steiner, I., Nothnagel, M., Alber, M., Geider, K., Laube, B., Schwake, M., Finsterwalder, K., Franke, A., Schilhabel, M., and 59 others. <strong>Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.</strong> Nature Genet. 45: 1067-1072, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23933819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23933819</a>] [<a href="https://doi.org/10.1038/ng.2728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23933819">Lemke et al. (2013)</a> identified a heterozygous c.2829C-G transversion in the GRIN2A gene, resulting in a tyr943-to-ter (Y943X) substitution. The mutation was also found in the patient's sib, who had febrile seizures and centrotemporal spikes on EEG, and in the patient's father, who had benign epilepsy of childhood with centrotemporal spikes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23933819" 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="Takano1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Takano, H., Onodera, O., Tanaka, H., Mori, H., Sakimura, K., Hori, T., Kobayashi, H., Mishina, M., Tsuji, S.
|
|
<strong>Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel.</strong>
|
|
Biochem. Biophys. Res. Commun. 197: 922-926, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8267632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8267632</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8267632" 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/10.1006/bbrc.1993.2567" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Wang2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, J., Liu, S., Fu, Y., Wang, J. H., Lu, Y.
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<strong>Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.</strong>
|
|
Nature Neurosci. 6: 1039-1047, 2003.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14502288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14502288</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14502288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nn1119" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Wei2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wei, X., Walia, V., Lin, J. C., Teer, J. K., Prickett, T. D., Gartner, J., Davis, S., NISC Comparative Sequencing Program, Stemke-Hale, K., Davies, M. A., Gershenwald, J. E., Robinson, W., Robinson, S., Rosenberg, S. A., Samuels, Y.
|
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<strong>Exome sequencing identifies GRIN2A as frequently mutated in melanoma.</strong>
|
|
Nature Genet. 43: 442-446, 2011.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21499247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21499247</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21499247[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=21499247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.810" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Wong2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wong, T. P., Liu, L., Sheng, M., Wang, Y. T.
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<strong>Response to comment on 'role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity'.</strong>
|
|
Science 305: 1912 only, 2004.
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</p>
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</div>
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</li>
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<li>
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<a id="34" class="mim-anchor"></a>
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<a id="Yan2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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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Science 370: eaay3302, 2020. Note: Electronic Article.
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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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</p>
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</div>
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</ol>
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<br />
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/03/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/18/2018<br>Ada Hamosh - updated : 08/11/2017<br>Cassandra L. Kniffin - updated : 11/5/2013<br>Ada Hamosh - updated : 2/12/2013<br>Patricia A. Hartz - updated : 2/23/2012<br>Cassandra L. Kniffin - updated : 5/16/2011<br>Cassandra L. Kniffin - updated : 5/12/2011<br>Ada Hamosh - updated : 6/16/2009<br>Ada Hamosh - updated : 12/6/2006<br>Cassandra L. Kniffin - updated : 4/3/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Ada Hamosh - updated : 11/21/2005<br>Ada Hamosh - updated : 3/3/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Ada Hamosh - updated : 8/30/2004<br>Ada Hamosh - updated : 6/9/2004<br>Cassandra L. Kniffin - updated : 10/10/2003<br>Stylianos E. Antonarakis - updated : 12/2/2002<br>Rebekah S. Rasooly - updated : 6/13/1998<br>Stylianos E. Antonarakis - updated : 3/21/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/25/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 05/16/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/03/2021<br>alopez : 02/24/2021<br>alopez : 10/18/2018<br>carol : 02/23/2018<br>alopez : 02/22/2018<br>alopez : 08/11/2017<br>carol : 11/08/2013<br>carol : 11/8/2013<br>ckniffin : 11/5/2013<br>carol : 2/12/2013<br>mgross : 3/7/2012<br>mgross : 3/7/2012<br>terry : 2/23/2012<br>wwang : 5/16/2011<br>carol : 5/13/2011<br>ckniffin : 5/12/2011<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>alopez : 12/15/2006<br>terry : 12/6/2006<br>wwang : 4/17/2006<br>ckniffin : 4/3/2006<br>wwang : 3/20/2006<br>ckniffin : 3/2/2006<br>alopez : 11/22/2005<br>terry : 11/21/2005<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>mgross : 1/10/2005<br>alopez : 9/1/2004<br>terry : 8/30/2004<br>alopez : 6/9/2004<br>terry : 6/9/2004<br>carol : 10/14/2003<br>ckniffin : 10/10/2003<br>mgross : 12/2/2002<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>carol : 11/4/1999<br>psherman : 9/2/1999<br>psherman : 6/13/1998<br>carol : 3/21/1998<br>carol : 3/25/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 138253
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2A; GRIN2A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT EPSILON-1; NMDAR2A<br />
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NR2A
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GRIN2A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 230438007;
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<strong>ICD10CM:</strong> G40.8;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 16p13.2
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:9,753,404-10,182,908 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
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16p13.2
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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Epilepsy, focal, with speech disorder and with or without impaired intellectual development
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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245570
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<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 GRIN2A (summary by Matta et al., 2011). </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>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Takano et al. (1993) had previously shown by molecular cloning and expression of cDNAs that the epsilon and zeta subfamilies of the mouse glutamate receptor channel subunits constitute NMDA receptor channels. The 4 members of the mouse epsilon subfamily, the E1, E2 (GRIN2B; 138252), E3 (GRIN2C; 138254), and E4 (GRIN2D; 602717) subunits, are distinct in distribution, functional properties, and regulation. Rat counterparts of the mouse E1, E2, E3, E4, and zeta-1 (Z1, or GRIN1) subunits had also been isolated and designated Nr2a, Nr2b, Nr2c, Nr2d, and Nmdar1, respectively (Monyer et al., 1992; Ishii et al., 1993). Takano et al. (1993) reported the molecular cloning of partial cDNA and genomic DNA clones encoding human NMDA receptor channel subunits. </p><p>By screening a human cerebellar cDNA library with a partial NMDAR2A cDNA generated by PCR using rat NMDAR2 sequences, Hess et al. (1996) cloned a full-length NMDAR2A cDNA. The predicted protein contains 1,464-amino acids. </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>Gene Structure</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Endele et al. (2010) noted that the GRIN2A gene contains 14 exons. </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>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By fluorescence in situ hybridization, Takano et al. (1993) mapped the genes for the E1 subunit to 16p13, the E3 subunit to 17q25, and the Z1 subunit to 9q34. Kalsi et al. (1998) refined the localization of the GRIN2A gene to 16p13.2 by PCR of a regional somatic cell hybrid mapping panel for chromosome 16. </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>Gene Function</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Hess et al. (1996) found that human NMDAR2A functioned as an NMDA receptor when coexpressed with NMDAR1 in Xenopus oocytes. </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>Lee et al. (2002) reported that dopamine D1 receptors (126449) modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A and NR2A. While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833)-dependent pathway. </p><p>Wang et al. (2003) showed that transient forebrain ischemia in rat caused hippocampal CA1 pyramidal neuron cell death. Ischemia in these cells led to an increase in p25, the truncated and deleterious form of the neuron-specific activator p35 (603460), which was associated with prolonged activation of cyclin-dependent kinase-5 (CDK5; 123831). Activated CDK5 phosphorylated the NMDA receptor-2A subunit at ser1232, resulting in enhanced current activity through NMDA synaptic receptors. Inhibition of CDK5 or of the interaction between CDK5 and NR2A protected CA1 pyramidal cells from ischemic insult. Wang et al. (2003) concluded that modulation of NMDA receptors by CDK5 is the primary intracellular event underlying ischemic injury of CA1 pyramidal neurons. </p><p>Using hippocampal slice preparations, Liu et al. (2004) showed that selectively blocking NMDA receptors that contain the NR2B subunit (138252) abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A-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>By examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, Popescu et al. (2004) showed that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predicted that, after binding neurotransmitter, receptors hesitate for approximately 4 milliseconds in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initial fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on the pulse frequency. </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, 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>Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists, but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. Micu et al. (2006) concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling. </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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</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>Biochemical Features</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>Crystal Structure</em></strong></p><p>
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Furukawa et al. (2005) reported the crystal structure of the ligand-binding core of NR2A with glutamate and that of the NR1 (GRIN1; 138249)-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defined the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiologic experiments, confirmed that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyr535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation. </p><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><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)/GluN2B (GRIN2B; 138252) 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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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</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>Reutlinger et al. (2010) reported 3 unrelated patients with different deletions of chromosome 16p13 including the GRIN2A gene who had early-onset focal epilepsy, severe intellectual disability, and lack of speech or delayed speech development (245570). EEG available from 2 patients showed centrotemporal spikes, reminiscent of Rolandic epilepsy, and electrical status epilepticus in sleep (ESES). All showed delayed global development from birth or early infancy. All had variable dysmorphic features, including low-set ears, epicanthal folds, hypertelorism, deep-set eyes, broad nasal tip, short nose, and brachydactyly. Genomewide screening for structural genomic variants identified 3 different deletions, ranging in size from 980 kb to 2.6 Mb, in the 3 patients. Two of the deletions were confirmed to be de novo; parental samples from the third patient were unavailable. The only gene located in the critical shared region of all 3 patients was GRIN2A. </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>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>Focal Epilepsy and Speech Disorder with or without Mental Retardation</em></strong></p><p>
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Heterozygous germline mutations in the GRIN2A gene have been found in focal epilepsy with speech disorder (FESD; 245570), a childhood-onset seizure disorder with a highly variable phenotype. FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by Lesca et al., 2013; Lemke et al., 2013; Carvill et al., 2013). </p><p>In 3 members of a German family with childhood onset of focal seizures associated with variable learning difficulties and mental retardation (245570), Endele et al. (2010) identified a heterozygous mutation in the GRIN2A gene (Q218X; 138253.0001). Another heterozygous de novo mutation (N615K; 138253.0002) was found in a 3-year-old French girl with severe mental retardation and early-onset epileptic spasms and myoclonic seizures. The 2 mutations had a frequency of 1 in 254 alleles from 127 patients with a history of epilepsy and/or abnormal EEG and variable degrees of mental retardation. These findings suggested that the GRIN2A gene is important for proper neuronal activity and development. Endele et al. (2010) suggested that GRIN2A mutations may lead to abnormal subunit function and affect neuronal ion flux and electrical transmission between neurons, resulting in developmental abnormalities. </p><p>By sequence analysis of the GRIN2A gene in 519 probands with a range of epileptic encephalopathies, Carvill et al. (2013) identified heterozygous mutations (138253.0005-138253.0007) in 4 probands, all of whom came from the cohort of 44 patients with epilepsy-aphasia syndromes (9% of probands with epilepsy-aphasia syndromes). One of the probands was from the family reported by Scheffer et al. (1995) with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia; a heterozygous splice site mutation (138253.0005) segregated with the disorder in all 7 patients in this family. Two affected members of an unrelated family with epileptic encephalopathy with continuous spike and wave in slow-wave sleep (CSWS) also carried this mutation. Both were Australian families of European descent, and haplotype analysis indicated a founder effect. Three sibs from another family with CSWS or intermediate epilepsy-aphasia disorder carried a different heterozygous mutation (138253.0007). The fourth family with a GRIN2A mutation was diagnosed with Landau-Kleffner syndrome (LKS). The findings indicated that GRIN2A mutations can be associated with a wide range of epilepsy-aphasia spectrum phenotypes. No GRIN2A mutations were found in 475 patients with other epileptic encephalopathy phenotypes or in 81 patients with benign epilepsy with centrotemporal spikes (BECTS). </p><p>Lesca et al. (2013) examined the role of the GRIN2A gene in 66 probands with LKS or CSWS. Heterozygous inherited or de novo mutations (see, e.g., 138253.0008-138253.0010) were found in 7 of 7 families and in 6 of 59 patients with sporadic disease. Segregation studies in the families showed that some mutation carriers had atypical rolandic epilepsy. Two mutation carriers reportedly had benign childhood epilepsy. Most mutation carriers had dysphasia or verbal dyspraxia. Some mutation carriers were unaffected, indicating incomplete penetrance. Heterozygous GRIN2A mutations were subsequently found in 2 families with atypical rolandic epilepsy. One family with a mutation in the SRPX2 gene (300642.0001; Roll et al., 2006; 300643) also carried a heterozygous GRIN2A mutation. In total, 14 point mutations and 2 small deletions involving the GRIN2A gene (15 kb and 75 kb, respectively) were identified. Functional studies showed that 2 of the missense mutations caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. GRIN2A mutations were located in different domains of the protein, and there were no apparent genotype/phenotype correlations. Lesca et al. (2013) concluded that GRIN2A mutations represent a major genetic determinant of LKS and CSWS, as well as related epileptic disorders in the same clinical continuum, such as atypical rolandic epilepsy and speech impairment. </p><p>Lemke et al. (2013) identified heterozygous mutations in the GRIN2A gene (see, e.g., 138253.0005; 138253.0011-138253.0012) in 27 (7.5%) of 359 patients from 2 independent cohorts with idiopathic focal epilepsy syndromes, including Landau-Kleffner syndrome, CSWS, atypical rolandic epilepsy, and benign epilepsy of childhood with centrotemporal spikes. Mutations occurred at a significantly higher frequency in patients compared to the Exome Variant Server (0.6%; p = 4.83 x 10(-18)) or in controls of European ancestry (p = 1.18 x 10(-16)). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12 (4.9%) of 245 individuals with BECTS to 9 (17.6%) of 51 with LKS/CSWS. Splice site, truncating, and frameshift mutations were more commonly associated with the more severe phenotypes, and missense mutations were more commonly associated with the more benign phenotypes. Segregation status was available for 18 families. The mutations segregated with a phenotype of different epileptic disorders within the families, ranging from BECTS to learning disabilities and intellectual disability to atypical rolandic epilepsy and CSWS; some mutations carriers were unaffected. Exon-disrupting microdeletions of the GRIN2A gene were also found in 3 (1%) of 286 individuals screened for copy number variations. The findings indicated that alterations of the GRIN2A gene are a major genetic risk factor for various types of idiopathic focal epilepsy. </p><p><strong><em>Variant Function</em></strong></p><p>
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Swanger et al. (2016) assessed variation across GRIN2A and GRIN2B (138252) 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 nonsynaptic 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><p><strong><em>Somatic Mutations in Melanoma</em></strong></p><p>
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Using exome sequencing, Wei et al. (2011) found somatic mutations in the GRIN2A gene in 6 of 14 melanoma (155600) samples. A further 11 somatic mutations were found in a prevalence screen of 38 additional melanomas, and the findings were validated in 2 more panel sets. Overall, there were 34 distinct GRIN2A mutations in 135 melanoma samples (25.2%). These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma. </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>Evolution</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>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including GRIN2A, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sakimura et al. (1995) showed that targeted disruption of the mouse Nmdar2a gene produced mice that were viable, although impaired hippocampal plasticity was observed in homozygous -/- mice. By gene targeting, Sprengel et al. (1998) generated mutant mice expressing the Nmdar2a gene without the large intracellular C-terminal domain. These mice were viable but exhibited impaired synaptic plasticity and contextual memory. The authors concluded that the observed phenotypes appear to reflect defective intracellular signaling. </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-N2R 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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</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 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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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GRIN2A, GLN218TER
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<br />
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SNP: rs387906637,
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ClinVar: RCV000022584
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 members of a German family with childhood seizures and variable neurodevelopmental defects ranging from mental retardation to learning difficulties (FESD; 245570), Endele et al. (2010) identified a heterozygous 652C-T transition in exon 4 of the GRIN2A gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation was not found in 360 control chromosomes, and the mutant transcript was degraded by nonsense-mediated mRNA decay. These findings indicated loss of function. </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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<h4>
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<span class="mim-font">
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<strong>.0002 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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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GRIN2A, ASN615LYS
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<br />
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SNP: rs397518447,
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ClinVar: RCV000022585
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old French girl early-onset epileptic spasms and myoclonic seizures and severe mental retardation (FESD; 245570), Endele et al. (2010) identified a de novo heterozygous 1845C-A transversion in exon 10 of the GRIN2A gene, resulting in an asn615-to-lys (N615K) substitution in a conserved residue of the membrane reentrant loop (P-loop). The mutation was not found in 1,080 control chromosomes. In vitro functional expression studies showed that the mutant receptor had decreased calcium permeability. Moreover, coexpression with the wildtype protein showed a dominant-negative effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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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GRIN2A, LEU649VAL
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<br />
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SNP: rs397514557,
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ClinVar: RCV000032866
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with severe intellectual disability, dysplastic corpus callosum, myelination delay, epilepsy, severe feeding problems, hypothyroidism, and mild facial dysmorphism (FESD; 245570), de Ligt et al. (2012) identified a de novo heterozygous 1945C-G transversion in the GRIN2A gene, resulting in a leu649-to-val (L649V) substitution. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</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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GRIN2A, PRO522ARG
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<br />
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|
SNP: rs397518450,
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ClinVar: RCV000032867, RCV001091973, RCV004629145
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with severe intellectual disability, no speech, epilepsy since 9 months of age, and spasticity (FESD; 245570), de Ligt et al. (2012) identified a de novo heterozygous 1655C-G transversion in the GRIN2A gene, resulting in a pro522-to-arg (P522R) substitution. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GRIN2A, IVS4DS, G-A, +1
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<br />
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SNP: rs397518465,
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ClinVar: RCV000074386, RCV000656049, RCV000726036, RCV002274908
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|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a family with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (FESD; 245570), originally reported by Scheffer et al. (1995), Carvill et al. (2013) identified a heterozygous G-to-A transition in intron 4 of the GRIN2A gene (c.1007+1G-A), predicted to result in the skipping of exon 4 and premature termination (Phe139IlefsTer15). The mutation was not found in 6,500 control exomes. The same heterozygous mutation was also found in a father and son with epileptic encephalopathy with continuous spike and wave in slow-wave sleep. Analysis of patient cells showed that the mutant transcript underwent nonsense-mediate mRNA decay. Both of the families were of European descent, and haplotype analysis indicated a founder effect. The findings suggested that GRIN2A mutations can cause a spectrum of epilepsy-aphasia phenotypes. </p><p>Lemke et al. (2013) identified a heterozygous c.1007+1G-A in 7 affected individuals from 3 unrelated families and in a singleton individual, all with variable manifestations of epilepsy, including Landau-Kleffner syndrome, continuous spike and waves during slow-wave sleep, atypical benign partial epilepsy, and benign epilepsy with centrotemporal spikes. Lemke et al. (2013) suggested that additional modifying factors might explain the phenotypic variability. </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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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GRIN2A, MET1THR
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<br />
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|
|
SNP: rs397518466,
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|
|
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|
|
|
|
ClinVar: RCV000074387, RCV004721258
|
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|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of Landau-Kleffner syndrome, Carvill et al. (2013) identified a heterozygous c.2T-C transition in the GRIN2A gene, resulting in a met1-to-thr (M1T) substitution. The mutation was predicted to have detrimental effects on protein synthesis, but RNA was not available. Their father, who had unclassified epilepsy and speech/language disorder, also carried the mutation. The mutation was not found in 6,500 control exomes. </p>
|
|
</span>
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|
</div>
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<div>
|
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<br />
|
|
</div>
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|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
GRIN2A, THR531MET
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|
|
<br />
|
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|
|
SNP: rs397518468,
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|
|
|
|
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|
|
ClinVar: RCV000074389, RCV001557828
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 sibs with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of epilepsy-aphasia disorder or continuous spike and waves during slow-wave sleep syndrome, Carvill et al. (2013) identified a heterozygous c.1592C-T transition in the GRIN2A gene, resulting in a thr531-to-met (T531M) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in 6,500 control exomes. Coexpression of the mutant protein with wildtype GRIN1 (138249) in COS-7 cells resulted in a shift in NMDA receptor kinetics, with a 4-fold increase in the mean duration of the open state compared to wildtype channels. The patients had onset between ages 6.5 and 11 years of focal dyscognitive or tonic-clonic seizures that remitted in 2 patients by age 11 years. The patients had variably delayed development, mild intellectual disability, and speech/language difficulties. EEG findings were all abnormal and differed slightly, including centrotemporal spikes, high-voltage discharges while awake, and continuous spike-waves during sleep. </p>
|
|
</span>
|
|
</div>
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2A, IVS5AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397518469,
|
|
|
|
|
|
|
|
ClinVar: RCV000074390
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation family with variable expression of focal epilepsy and speech disorder (FESD; 245570), including clinical diagnoses of continuous spike and waves during slow-wave sleep (CSWS), Landau-Kleffner syndrome, and atypical rolandic epilepsy, Lesca et al. (2013) identified a heterozygous A-to-G transition in intron 5 of the GRIN2A gene (c.1123-2A-G), resulting in the skipping of exon 5 and premature termination (Val375fsTer). One mutation carrier was unaffected, suggesting incomplete penetrance. The findings were consistent with haploinsufficiency as the pathogenic effect. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2A, ARG518HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397518470,
|
|
|
|
|
|
|
|
ClinVar: RCV000074391, RCV000379543
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lesca et al. (2013) identified a heterozygous c.1553G-A transition in the GRIN2A gene, resulting in an arg518-to-his (R518H) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes, or Exome Variant Server databases. The mutation was also present in the patient's brother, who had atypical rolandic epilepsy with dysphasia, and the father, who had verbal dyspraxia but no seizures. Another sib of the proband, who did not carry the mutation, had centrotemporal spikes on EEG without seizures, thus representing a phenocopy. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2A, PHE652VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397518471,
|
|
|
|
|
|
|
|
ClinVar: RCV000074392
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with focal epilepsy and speech disorder (FESD; 245570) and autistic features, with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lesca et al. (2013) identified a de novo heterozygous c.1954T-G transversion in the GRIN2A gene, resulting in a phe652-to-val (F652V) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2A, ARG681TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397518472,
|
|
|
|
|
|
|
|
ClinVar: RCV000074393, RCV000260469
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of Landau-Kleffner syndrome, Lemke et al. (2013) identified a heterozygous c.2941C-T transition in the GRIN2A gene, resulting in an arg681-to-ter (R681X) substitution. The patient had a learning disability and language disorder. Family history showed that 2 relatives with learning disabilities also carried the mutation, as did an unaffected individual. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
GRIN2A, TYR943TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397518467,
|
|
|
|
|
|
|
|
ClinVar: RCV000074388
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with focal epilepsy and speech disorder with mental retardation (FESD; 245570), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lemke et al. (2013) identified a heterozygous c.2829C-G transversion in the GRIN2A gene, resulting in a tyr943-to-ter (Y943X) substitution. The mutation was also found in the patient's sib, who had febrile seizures and centrotemporal spikes on EEG, and in the patient's father, who had benign epilepsy of childhood with centrotemporal spikes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
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|
|
|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others.
|
|
<strong>GRIN2A mutations cause epilepsy-aphasia spectrum disorders.</strong>
|
|
Nature Genet. 45: 1073-1076, 2013.
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|
|
[PubMed: 23933818]
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[Full Text: https://doi.org/10.1038/ng.2727]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
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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<strong>Diagnostic exome sequencing in persons with severe intellectual disability.</strong>
|
|
New Eng. J. Med. 367: 1921-1929, 2012.
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[PubMed: 23033978]
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[Full Text: https://doi.org/10.1056/NEJMoa1206524]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
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.
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|
[PubMed: 16537520]
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|
|
[Full Text: https://doi.org/10.1073/pnas.0510212103]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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.
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|
[PubMed: 11689882]
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|
|
[Full Text: https://doi.org/10.1038/nm1101-1189]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T.
|
|
<strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong>
|
|
Cell 119: 1027-1040, 2004.
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|
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|
|
[PubMed: 15620360]
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|
|
[Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 20890276]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.677]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Furukawa, H., Singh, S. K., Mancusso, R., Gouaux, E.
|
|
<strong>Subunit arrangement and function in NMDA receptors.</strong>
|
|
Nature 438: 185-192, 2005.
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|
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|
|
|
[PubMed: 16281028]
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|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature04089]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gielen, M., Siegler Retchless, B., 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: 19404260]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature07993]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
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.
|
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/03/2021<br>Ada Hamosh - updated : 10/18/2018<br>Ada Hamosh - updated : 08/11/2017<br>Cassandra L. Kniffin - updated : 11/5/2013<br>Ada Hamosh - updated : 2/12/2013<br>Patricia A. Hartz - updated : 2/23/2012<br>Cassandra L. Kniffin - updated : 5/16/2011<br>Cassandra L. Kniffin - updated : 5/12/2011<br>Ada Hamosh - updated : 6/16/2009<br>Ada Hamosh - updated : 12/6/2006<br>Cassandra L. Kniffin - updated : 4/3/2006<br>Cassandra L. Kniffin - updated : 3/2/2006<br>Ada Hamosh - updated : 11/21/2005<br>Ada Hamosh - updated : 3/3/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Ada Hamosh - updated : 8/30/2004<br>Ada Hamosh - updated : 6/9/2004<br>Cassandra L. Kniffin - updated : 10/10/2003<br>Stylianos E. Antonarakis - updated : 12/2/2002<br>Rebekah S. Rasooly - updated : 6/13/1998<br>Stylianos E. Antonarakis - updated : 3/21/1998
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Victor A. McKusick : 3/25/1994
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alopez : 05/16/2022<br>mgross : 03/03/2021<br>alopez : 02/24/2021<br>alopez : 10/18/2018<br>carol : 02/23/2018<br>alopez : 02/22/2018<br>alopez : 08/11/2017<br>carol : 11/08/2013<br>carol : 11/8/2013<br>ckniffin : 11/5/2013<br>carol : 2/12/2013<br>mgross : 3/7/2012<br>mgross : 3/7/2012<br>terry : 2/23/2012<br>wwang : 5/16/2011<br>carol : 5/13/2011<br>ckniffin : 5/12/2011<br>alopez : 6/17/2009<br>terry : 6/16/2009<br>alopez : 12/15/2006<br>terry : 12/6/2006<br>wwang : 4/17/2006<br>ckniffin : 4/3/2006<br>wwang : 3/20/2006<br>ckniffin : 3/2/2006<br>alopez : 11/22/2005<br>terry : 11/21/2005<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>mgross : 1/10/2005<br>alopez : 9/1/2004<br>terry : 8/30/2004<br>alopez : 6/9/2004<br>terry : 6/9/2004<br>carol : 10/14/2003<br>ckniffin : 10/10/2003<br>mgross : 12/2/2002<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>carol : 11/4/1999<br>psherman : 9/2/1999<br>psherman : 6/13/1998<br>carol : 3/21/1998<br>carol : 3/25/1994
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