3064 lines
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- *602717 - GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2D; GRIN2D
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<p>
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<span class="h4">*602717</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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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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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602717">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<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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<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=ENSG00000105464;t=ENST00000263269" 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=2906" 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=602717" 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="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=ENSG00000105464;t=ENST00000263269" 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_000836,XM_011526872" 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_000836" 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=602717" 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=04095&isoform_id=04095_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/GRIN2D" 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/2444026,62088164,119572731,153946391,229462910,768008644" 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/O15399" 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=2906" 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=ENSG00000105464;t=ENST00000263269" 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=GRIN2D" 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=GRIN2D" 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+2906" 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/GRIN2D" 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:2906" 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/2906" 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=chr19&hgg_gene=ENST00000263269.4&hgg_start=48393668&hgg_end=48444931&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/genes/HGNC:4588" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602717[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 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=602717[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/GRIN2D/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/ENSG00000105464" 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=GRIN2D" 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=GRIN2D" 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=GRIN2D" 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=GRIN2D&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/PA28982" 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:4588" 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:95823" 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/GRIN2D#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:95823" 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/2906/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=2906" 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-041008-124" 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:2906" 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=GRIN2D&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602717
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2D; GRIN2D
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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N-METHYL-D-ASPARTATE RECEPTOR CHANNEL, SUBUNIT EPSILON-4; NMDAR2D
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GRIN2D" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GRIN2D</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/19/895?start=-3&limit=10&highlight=895">19q13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:48393668-48444931&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'})">19:48,393,668-48,444,931</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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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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<a href="/geneMap/19/895?start=-3&limit=10&highlight=895">
|
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19q13.33
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 46
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/617162"> 617162 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/602717" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/602717" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<p>Neuronal signals elicited by glutamate are processed by ionotropic and metabotropic subtypes of receptors. The ionotropic receptor group contains integral cation-specific ion channels and is further subdivided into 2 types, N-methyl-D-aspartate (NMDA) and non-NMDA receptors. NMDA receptor channels are heteromers composed of the key receptor subunit NMDAR1 (GRIN1; <a href="/entry/138249">138249</a>) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A; <a href="/entry/138253">138253</a>), NMDAR2B (GRIN2B; <a href="/entry/138252">138252</a>), NMDAR2C (GRIN2C; <a href="/entry/138254">138254</a>), and NMDAR2D (GRIN2D).</p>
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<p>By screening a human fetal brain cDNA library with an NMDAR2A cDNA, <a href="#3" class="mim-tip-reference" title="Hess, S. D., Daggett, L. P., Deal, C., Lu, C.-C., Johnson, E. C., Velicelebi, G. <strong>Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors.</strong> J. Neurochem. 70: 1269-1279, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9489750</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1998.70031269.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9489750">Hess et al. (1998)</a> isolated cDNAs encoding NMDAR2D. The sequence of the predicted 1,336-amino acid human NMDAR2D protein is 95% identical to that of rat Nmdar2d. NMDAR1/NMDAR2D receptors expressed in Xenopus oocytes and mammalian cells displayed a pharmacologic and biophysical profile distinct from those of other human recombinant NMDA receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9489750" 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 use of the CpG-GBS method, <a href="#8" class="mim-tip-reference" title="Watanabe, T., Inoue, S., Hiroi, H., Orimo, A., Kawashima, H., Muramatsu, M. <strong>Isolation of estrogen-responsive genes with a CpG island library.</strong> Molec. Cell. Biol. 18: 442-449, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9418891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9418891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9418891[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/10.1128/MCB.18.1.442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9418891">Watanabe et al. (1998)</a> isolated 3 estrogen-responsive genes, including GRIN2D, which they called EB11. Northern blot analysis detected expression of a 6.0-kb transcript in an osteosarcoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9418891" 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 radiation hybrid analysis, <a href="#5" 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> mapped the human GRIN2D gene to 19q13.1-qter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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="#2" 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>
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<p><a href="#1" 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="#1" 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>
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<p>In 2 unrelated girls with developmental and epileptic encephalopathy-46 (DEE46; <a href="/entry/617162">617162</a>), <a href="#6" class="mim-tip-reference" title="Li, D., Yuan, H., Ortiz-Gonzalez, X. R., Marsh, E. D., Tian, L., McCormick, E. M., Kosobucki, G. J., Chen, W., Schulien, A. J., Chiavacci, R., Tankovic, A., Naase, C., and 12 others. <strong>GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.</strong> Am. J. Hum. Genet. 99: 802-816, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27616483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27616483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27616483[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.2016.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27616483">Li et al. (2016)</a> identified a de novo heterozygous missense mutation in the GRIN2D gene (V667I; <a href="#0001">602717.0001</a>). The mutation was found by whole-exome sequencing in the first patient and by sequencing of a targeted epilepsy gene panel in the second patient. In vitro functional expression studies showed that the mutation resulted in a significant gain-of-function effect with enhanced activation of the NMDA receptor and neurotoxicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27616483" 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 unrelated patients with DEE46, <a href="#7" class="mim-tip-reference" title="Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N. <strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong> Clin. Genet. 94: 538-547, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30280376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30280376</a>] [<a href="https://doi.org/10.1111/cge.13454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30280376">Tsuchida et al. (2018)</a> identified heterozygous missense mutations in the GRIN2D gene (<a href="#0002">602717.0002</a>-<a href="#0004">602717.0004</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in available parental samples. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30280376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Ikeda, K., Araki, K., Takayama, C., Inoue, Y., Yagi, T., Aizawa, S., Mishina, M. <strong>Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel.</strong> Brain Res. Molec. Brain Res. 33: 61-71, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774946</a>] [<a href="https://doi.org/10.1016/0169-328x(95)00107-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8774946">Ikeda et al. (1995)</a> generated mice defective in the epsilon-4 subunit of the NMDA receptor channel by targeted disruption of the Nmdar2d gene. The mutant mice exhibited normal behavior in motor activity and anxiety tests but showed reduced spontaneous activity in an open field test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886040861 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886040861;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=rs886040861" 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=rs886040861" 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=RCV000257970" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000257970" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000257970</a>
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<p>In 2 unrelated girls with developmental and epileptic encephalopathy-46 (DEE46; <a href="/entry/617162">617162</a>), <a href="#6" class="mim-tip-reference" title="Li, D., Yuan, H., Ortiz-Gonzalez, X. R., Marsh, E. D., Tian, L., McCormick, E. M., Kosobucki, G. J., Chen, W., Schulien, A. J., Chiavacci, R., Tankovic, A., Naase, C., and 12 others. <strong>GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.</strong> Am. J. Hum. Genet. 99: 802-816, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27616483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27616483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27616483[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.2016.07.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27616483">Li et al. (2016)</a> identified a de novo heterozygous c.1999G-A transition (c.1999G-A, NM_000836.2) in the GRIN2D gene, resulting in a val667-to-ile (V667I) substitution at a highly conserved residue in the M3 transmembrane domain that forms the ion channel core. The mutation was found by whole-exome sequencing in the first patient and by sequencing of a targeted epilepsy gene panel in the second patient. It was not found in the 1000 Genomes Project, Exome Sequencing Project (6500SI), or ExAC (v.0.3) databases, or in an in-house database of over 2,000 samples. Voltage clamp studies in transfected Xenopus oocytes and HEK293 cells showed that the mutation increased the receptor responsiveness to glutamate and glycine agonists, decreased the sensitivity of the channel to negative allosteric modulators, prolonged the deactivation time, and increased the channel opening probability, all consistent with a gain-of-function effect on the NMDA receptor. Transfection of the mutation into rat cortical neurons resulted in increased neuronal excitotoxicity that could be blocked by the NMDAR antagonist memantine. The patients had onset of intractable seizures at 2 and 4 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27616483" 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 an 8-year-old Japanese boy (patient 1) with developmental and epileptic encephalopathy-46 (DEE46; <a href="/entry/617162">617162</a>), <a href="#7" class="mim-tip-reference" title="Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N. <strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong> Clin. Genet. 94: 538-547, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30280376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30280376</a>] [<a href="https://doi.org/10.1111/cge.13454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30280376">Tsuchida et al. (2018)</a> identified a de novo heterozygous c.2043G-C transversion (c.2043G-C, NM_000836.2) in the GRIN2D gene, resulting in a met681-to-ile (M681I) substitution at a highly conserved residue in the M3 channel-forming transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. Functional studies of the variant and studies of patient cells were not performed. The patient showed developmental delay at 9 months of age and had onset of intractable seizures at 2 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30280376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569065866 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569065866;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=rs1569065866" 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=rs1569065866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 15-year-old Japanese girl (patient 2) with developmental and epileptic encephalopathy-46 (DEE46; <a href="/entry/617162">617162</a>), <a href="#7" class="mim-tip-reference" title="Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N. <strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong> Clin. Genet. 94: 538-547, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30280376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30280376</a>] [<a href="https://doi.org/10.1111/cge.13454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30280376">Tsuchida et al. (2018)</a> identified a heterozygous c.2080A-C transversion (c.2080A-C, NM_000836.2) in the GRIN2D gene, resulting in a ser694-to-arg (S694R) substitution at a highly conserved residue in one of the ligand-binding domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. The variant was not present in the mother. Functional studies of the variant and studies of patient cells were not performed. The patient was noted to have developmental delay at 2 years of age. She had onset of tonic and atonic seizures at 3 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30280376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46</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">rs1569064110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569064110;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=rs1569064110" 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=rs1569064110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old Malaysian boy (patient 3) with developmental and epileptic encephalopathy-46 (DEE46; <a href="/entry/617162">617162</a>), <a href="#7" class="mim-tip-reference" title="Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N. <strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong> Clin. Genet. 94: 538-547, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30280376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30280376</a>] [<a href="https://doi.org/10.1111/cge.13454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30280376">Tsuchida et al. (2018)</a> identified a heterozygous c.1345G-A transition (c.1345G-A, NM_000836.2) in the GRIN2D gene, resulting in an asp449-to-asn (D449N) substitution at a highly conserved residue in one of the ligand-binding domains. Parental samples were not available for study. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of seizures at 3 days of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30280376" 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>Mechanism of differential control of NMDA receptor activity by NR2 subunits.</strong>
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07993" target="_blank">Full Text</a>]
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Nature Neurosci. 5: 405-414, 2002.
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[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://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'})">related citations</a>]
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Hess, S. D., Daggett, L. P., Deal, C., Lu, C.-C., Johnson, E. C., Velicelebi, G.
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<strong>Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors.</strong>
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J. Neurochem. 70: 1269-1279, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9489750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9489750</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9489750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel.</strong>
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Brain Res. Molec. Brain Res. 33: 61-71, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8774946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8774946</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8774946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Kalsi, G., Whiting, P., Le Bourdelles, B., Callen, D., Barnard, E. A., Gurling, H.
|
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<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>
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Genomics 47: 423-425, 1998.
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[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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9480759" 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/geno.1997.5132" 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="6" class="mim-anchor"></a>
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<a id="Li2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Li, D., Yuan, H., Ortiz-Gonzalez, X. R., Marsh, E. D., Tian, L., McCormick, E. M., Kosobucki, G. J., Chen, W., Schulien, A. J., Chiavacci, R., Tankovic, A., Naase, C., and 12 others.
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<strong>GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.</strong>
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Am. J. Hum. Genet. 99: 802-816, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27616483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27616483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27616483[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=27616483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2016.07.013" 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="7" class="mim-anchor"></a>
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<a id="Tsuchida2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N.
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<strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong>
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Clin. Genet. 94: 538-547, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30280376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30280376</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30280376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13454" 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="8" class="mim-anchor"></a>
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<a id="Watanabe1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watanabe, T., Inoue, S., Hiroi, H., Orimo, A., Kawashima, H., Muramatsu, M.
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<strong>Isolation of estrogen-responsive genes with a CpG island library.</strong>
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Molec. Cell. Biol. 18: 442-449, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9418891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9418891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9418891[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=9418891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.18.1.442" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/15/2019
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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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Cassandra L. Kniffin - updated : 10/18/2016<br>Ada Hamosh - updated : 6/16/2009<br>Paul J. Converse - updated : 3/26/2001<br>Paul J. Converse - updated : 3/23/2001
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</span>
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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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Rebekah S. Rasooly : 6/12/1998
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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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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alopez : 11/19/2020<br>alopez : 11/10/2020<br>joanna : 10/18/2020<br>carol : 01/16/2019<br>carol : 01/15/2019<br>ckniffin : 01/15/2019<br>carol : 10/19/2016<br>ckniffin : 10/18/2016<br>alopez : 06/17/2009<br>terry : 6/16/2009<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 : 3/26/2001<br>terry : 3/23/2001<br>psherman : 9/2/1999<br>psherman : 6/24/1998<br>psherman : 6/13/1998<br>psherman : 6/12/1998
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</span>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602717
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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 2D; GRIN2D
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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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-4; NMDAR2D
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GRIN2D</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 19q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:48,393,668-48,444,931 </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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<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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19q13.33
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</td>
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<td>
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<span class="mim-font">
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Developmental and epileptic encephalopathy 46
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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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617162
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal 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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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Neuronal signals elicited by glutamate are processed by ionotropic and metabotropic subtypes of receptors. The ionotropic receptor group contains integral cation-specific ion channels and is further subdivided into 2 types, N-methyl-D-aspartate (NMDA) and non-NMDA receptors. NMDA receptor channels are heteromers composed of the key receptor subunit NMDAR1 (GRIN1; 138249) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A; 138253), NMDAR2B (GRIN2B; 138252), NMDAR2C (GRIN2C; 138254), and NMDAR2D (GRIN2D).</p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening a human fetal brain cDNA library with an NMDAR2A cDNA, Hess et al. (1998) isolated cDNAs encoding NMDAR2D. The sequence of the predicted 1,336-amino acid human NMDAR2D protein is 95% identical to that of rat Nmdar2d. NMDAR1/NMDAR2D receptors expressed in Xenopus oocytes and mammalian cells displayed a pharmacologic and biophysical profile distinct from those of other human recombinant NMDA receptors. </p><p>By use of the CpG-GBS method, Watanabe et al. (1998) isolated 3 estrogen-responsive genes, including GRIN2D, which they called EB11. Northern blot analysis detected expression of a 6.0-kb transcript in an osteosarcoma cell line. </p>
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</span>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Kalsi et al. (1998) mapped the human GRIN2D gene to 19q13.1-qter. </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 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>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>
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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>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>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>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 unrelated girls with developmental and epileptic encephalopathy-46 (DEE46; 617162), Li et al. (2016) identified a de novo heterozygous missense mutation in the GRIN2D gene (V667I; 602717.0001). The mutation was found by whole-exome sequencing in the first patient and by sequencing of a targeted epilepsy gene panel in the second patient. In vitro functional expression studies showed that the mutation resulted in a significant gain-of-function effect with enhanced activation of the NMDA receptor and neurotoxicity. </p><p>In 3 unrelated patients with DEE46, Tsuchida et al. (2018) identified heterozygous missense mutations in the GRIN2D gene (602717.0002-602717.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in available parental samples. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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<div>
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<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>Ikeda et al. (1995) generated mice defective in the epsilon-4 subunit of the NMDA receptor channel by targeted disruption of the Nmdar2d gene. The mutant mice exhibited normal behavior in motor activity and anxiety tests but showed reduced spontaneous activity in an open field test. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>4 Selected Examples):</strong>
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<strong>.0001 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46</strong>
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GRIN2D, VAL667ILE
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SNP: rs886040861,
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ClinVar: RCV000257970
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<p>In 2 unrelated girls with developmental and epileptic encephalopathy-46 (DEE46; 617162), Li et al. (2016) identified a de novo heterozygous c.1999G-A transition (c.1999G-A, NM_000836.2) in the GRIN2D gene, resulting in a val667-to-ile (V667I) substitution at a highly conserved residue in the M3 transmembrane domain that forms the ion channel core. The mutation was found by whole-exome sequencing in the first patient and by sequencing of a targeted epilepsy gene panel in the second patient. It was not found in the 1000 Genomes Project, Exome Sequencing Project (6500SI), or ExAC (v.0.3) databases, or in an in-house database of over 2,000 samples. Voltage clamp studies in transfected Xenopus oocytes and HEK293 cells showed that the mutation increased the receptor responsiveness to glutamate and glycine agonists, decreased the sensitivity of the channel to negative allosteric modulators, prolonged the deactivation time, and increased the channel opening probability, all consistent with a gain-of-function effect on the NMDA receptor. Transfection of the mutation into rat cortical neurons resulted in increased neuronal excitotoxicity that could be blocked by the NMDAR antagonist memantine. The patients had onset of intractable seizures at 2 and 4 months of age. </p>
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<strong>.0002 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46</strong>
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</span>
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</h4>
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GRIN2D, MET681ILE
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SNP: rs1569065861,
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ClinVar: RCV000736015
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<p>In an 8-year-old Japanese boy (patient 1) with developmental and epileptic encephalopathy-46 (DEE46; 617162), Tsuchida et al. (2018) identified a de novo heterozygous c.2043G-C transversion (c.2043G-C, NM_000836.2) in the GRIN2D gene, resulting in a met681-to-ile (M681I) substitution at a highly conserved residue in the M3 channel-forming transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. Functional studies of the variant and studies of patient cells were not performed. The patient showed developmental delay at 9 months of age and had onset of intractable seizures at 2 years of age. </p>
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</span>
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<span class="mim-font">
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<strong>.0003 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46</strong>
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GRIN2D, SER694ARG
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<br />
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SNP: rs1569065866,
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ClinVar: RCV000736016
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<p>In a 15-year-old Japanese girl (patient 2) with developmental and epileptic encephalopathy-46 (DEE46; 617162), Tsuchida et al. (2018) identified a heterozygous c.2080A-C transversion (c.2080A-C, NM_000836.2) in the GRIN2D gene, resulting in a ser694-to-arg (S694R) substitution at a highly conserved residue in one of the ligand-binding domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. The variant was not present in the mother. Functional studies of the variant and studies of patient cells were not performed. The patient was noted to have developmental delay at 2 years of age. She had onset of tonic and atonic seizures at 3 years of age. </p>
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<span class="mim-font">
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<strong>.0004 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 46</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GRIN2D, ASP449ASN
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<br />
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SNP: rs1569064110,
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ClinVar: RCV000736017
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<span class="mim-text-font">
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<p>In an 8-year-old Malaysian boy (patient 3) with developmental and epileptic encephalopathy-46 (DEE46; 617162), Tsuchida et al. (2018) identified a heterozygous c.1345G-A transition (c.1345G-A, NM_000836.2) in the GRIN2D gene, resulting in an asp449-to-asn (D449N) substitution at a highly conserved residue in one of the ligand-binding domains. Parental samples were not available for study. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database or in 575 Japanese controls. Functional studies of the variant and studies of patient cells were not performed. The patient had onset of seizures at 3 days of age. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J. W., Paoletti, P.
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<strong>Mechanism of differential control of NMDA receptor activity by NR2 subunits.</strong>
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Nature 459: 703-707, 2009.
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[PubMed: 19404260]
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[Full Text: https://doi.org/10.1038/nature07993]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hardingham, G. E., Fukunaga, Y., Bading, H.
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<strong>Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.</strong>
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Nature Neurosci. 5: 405-414, 2002.
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[PubMed: 11953750]
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[Full Text: https://doi.org/10.1038/nn835]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hess, S. D., Daggett, L. P., Deal, C., Lu, C.-C., Johnson, E. C., Velicelebi, G.
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<strong>Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors.</strong>
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J. Neurochem. 70: 1269-1279, 1998.
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[PubMed: 9489750]
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[Full Text: https://doi.org/10.1046/j.1471-4159.1998.70031269.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ikeda, K., Araki, K., Takayama, C., Inoue, Y., Yagi, T., Aizawa, S., Mishina, M.
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<strong>Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel.</strong>
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Brain Res. Molec. Brain Res. 33: 61-71, 1995.
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[PubMed: 8774946]
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[Full Text: https://doi.org/10.1016/0169-328x(95)00107-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kalsi, G., Whiting, P., Le Bourdelles, B., Callen, D., Barnard, E. A., Gurling, H.
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<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>
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Genomics 47: 423-425, 1998.
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[PubMed: 9480759]
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[Full Text: https://doi.org/10.1006/geno.1997.5132]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, D., Yuan, H., Ortiz-Gonzalez, X. R., Marsh, E. D., Tian, L., McCormick, E. M., Kosobucki, G. J., Chen, W., Schulien, A. J., Chiavacci, R., Tankovic, A., Naase, C., and 12 others.
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<strong>GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.</strong>
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Am. J. Hum. Genet. 99: 802-816, 2016.
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[PubMed: 27616483]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.07.013]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tsuchida, N., Hamada, K., Shiina, M., Kato, M., Kobayashi, Y., Tohyama, J., Kimura, K., Hoshino, K., Ganesan, V., Teik, K. W., Nakashima, M., Mitsuhashi, S., Mizuguchi, T., Takata, A., Miyake, N., Saitsu, H., Ogata, K., Miyatake, S., Matsumoto, N.
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<strong>GRIN2D variants in three cases of developmental and epileptic encephalopathy.</strong>
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Clin. Genet. 94: 538-547, 2018.
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[PubMed: 30280376]
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[Full Text: https://doi.org/10.1111/cge.13454]
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</li>
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<li>
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<p class="mim-text-font">
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Watanabe, T., Inoue, S., Hiroi, H., Orimo, A., Kawashima, H., Muramatsu, M.
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<strong>Isolation of estrogen-responsive genes with a CpG island library.</strong>
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Molec. Cell. Biol. 18: 442-449, 1998.
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[PubMed: 9418891]
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[Full Text: https://doi.org/10.1128/MCB.18.1.442]
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Cassandra L. Kniffin - updated : 01/15/2019<br>Cassandra L. Kniffin - updated : 10/18/2016<br>Ada Hamosh - updated : 6/16/2009<br>Paul J. Converse - updated : 3/26/2001<br>Paul J. Converse - updated : 3/23/2001
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Rebekah S. Rasooly : 6/12/1998
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alopez : 05/16/2022<br>alopez : 11/19/2020<br>alopez : 11/10/2020<br>joanna : 10/18/2020<br>carol : 01/16/2019<br>carol : 01/15/2019<br>ckniffin : 01/15/2019<br>carol : 10/19/2016<br>ckniffin : 10/18/2016<br>alopez : 06/17/2009<br>terry : 6/16/2009<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 : 3/26/2001<br>terry : 3/23/2001<br>psherman : 9/2/1999<br>psherman : 6/24/1998<br>psherman : 6/13/1998<br>psherman : 6/12/1998
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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