Alternative titles; symbols
HGNC Approved Gene Symbol: GRIN2D
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:48,393,668-48,444,931 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Developmental and epileptic encephalopathy 46 | 617162 | Autosomal dominant | 3 |
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).
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.
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.
By radiation hybrid analysis, Kalsi et al. (1998) mapped the human GRIN2D gene to 19q13.1-qter.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J. W., Paoletti, P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459: 703-707, 2009. [PubMed: 19404260] [Full Text: https://doi.org/10.1038/nature07993]
Hardingham, G. E., Fukunaga, Y., Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5: 405-414, 2002. [PubMed: 11953750] [Full Text: https://doi.org/10.1038/nn835]
Hess, S. D., Daggett, L. P., Deal, C., Lu, C.-C., Johnson, E. C., Velicelebi, G. Functional characterization of human N-methyl-D-aspartate subtype 1A/2D receptors. J. Neurochem. 70: 1269-1279, 1998. [PubMed: 9489750] [Full Text: https://doi.org/10.1046/j.1471-4159.1998.70031269.x]
Ikeda, K., Araki, K., Takayama, C., Inoue, Y., Yagi, T., Aizawa, S., Mishina, M. Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel. Brain Res. Molec. Brain Res. 33: 61-71, 1995. [PubMed: 8774946] [Full Text: https://doi.org/10.1016/0169-328x(95)00107-4]
Kalsi, G., Whiting, P., Le Bourdelles, B., Callen, D., Barnard, E. A., Gurling, H. 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. Genomics 47: 423-425, 1998. [PubMed: 9480759] [Full Text: https://doi.org/10.1006/geno.1997.5132]
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. GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Am. J. Hum. Genet. 99: 802-816, 2016. [PubMed: 27616483] [Full Text: https://doi.org/10.1016/j.ajhg.2016.07.013]
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. GRIN2D variants in three cases of developmental and epileptic encephalopathy. Clin. Genet. 94: 538-547, 2018. [PubMed: 30280376] [Full Text: https://doi.org/10.1111/cge.13454]
Watanabe, T., Inoue, S., Hiroi, H., Orimo, A., Kawashima, H., Muramatsu, M. Isolation of estrogen-responsive genes with a CpG island library. Molec. Cell. Biol. 18: 442-449, 1998. [PubMed: 9418891] [Full Text: https://doi.org/10.1128/MCB.18.1.442]