Alternative titles; symbols
HGNC Approved Gene Symbol: GRIN2A
SNOMEDCT: 230438007; ICD10CM: G40.8;
Cytogenetic location: 16p13.2 Genomic coordinates (GRCh38): 16:9,753,404-10,182,908 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.2 | Epilepsy, focal, with speech disorder and with or without impaired intellectual development | 245570 | Autosomal dominant | 3 |
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated ion channel permeable to Na+, K+, and Ca(2+) and is found at excitatory synapses throughout the brain. NMDA receptors are heterotetramers composed of 2 NMDA receptor-1 (NR1, or GRIN1; 138249) subunits and 2 NR2 subunits, such as GRIN2A (summary by Matta et al., 2011).
Takano et al. (1993) had previously shown by molecular cloning and expression of cDNAs that the epsilon and zeta subfamilies of the mouse glutamate receptor channel subunits constitute NMDA receptor channels. The 4 members of the mouse epsilon subfamily, the E1, E2 (GRIN2B; 138252), E3 (GRIN2C; 138254), and E4 (GRIN2D; 602717) subunits, are distinct in distribution, functional properties, and regulation. Rat counterparts of the mouse E1, E2, E3, E4, and zeta-1 (Z1, or GRIN1) subunits had also been isolated and designated Nr2a, Nr2b, Nr2c, Nr2d, and Nmdar1, respectively (Monyer et al., 1992; Ishii et al., 1993). Takano et al. (1993) reported the molecular cloning of partial cDNA and genomic DNA clones encoding human NMDA receptor channel subunits.
By screening a human cerebellar cDNA library with a partial NMDAR2A cDNA generated by PCR using rat NMDAR2 sequences, Hess et al. (1996) cloned a full-length NMDAR2A cDNA. The predicted protein contains 1,464-amino acids.
Endele et al. (2010) noted that the GRIN2A gene contains 14 exons.
By fluorescence in situ hybridization, Takano et al. (1993) mapped the genes for the E1 subunit to 16p13, the E3 subunit to 17q25, and the Z1 subunit to 9q34. Kalsi et al. (1998) refined the localization of the GRIN2A gene to 16p13.2 by PCR of a regional somatic cell hybrid mapping panel for chromosome 16.
Hess et al. (1996) found that human NMDAR2A functioned as an NMDA receptor when coexpressed with NMDAR1 in Xenopus oocytes.
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.
Lee et al. (2002) reported that dopamine D1 receptors (126449) modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A and NR2A. While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Wang et al. (2003) showed that transient forebrain ischemia in rat caused hippocampal CA1 pyramidal neuron cell death. Ischemia in these cells led to an increase in p25, the truncated and deleterious form of the neuron-specific activator p35 (603460), which was associated with prolonged activation of cyclin-dependent kinase-5 (CDK5; 123831). Activated CDK5 phosphorylated the NMDA receptor-2A subunit at ser1232, resulting in enhanced current activity through NMDA synaptic receptors. Inhibition of CDK5 or of the interaction between CDK5 and NR2A protected CA1 pyramidal cells from ischemic insult. Wang et al. (2003) concluded that modulation of NMDA receptors by CDK5 is the primary intracellular event underlying ischemic injury of CA1 pyramidal neurons.
Using hippocampal slice preparations, Liu et al. (2004) showed that selectively blocking NMDA receptors that contain the NR2B subunit (138252) abolished the induction of long-term depression but not long-term potentiation. In contrast, preferential inhibition of NR2A-containing NMDA receptors prevented the induction of long-term potentiation without affecting long-term depression production. Liu et al. (2004) concluded that their results demonstrated that distinct NMDA receptor subunits are critical factors that determine the polarity of synaptic plasticity.
Rusakov et al. (2004) commented on the paper by Liu et al. (2004), suggesting that because NR2B, but not NR2A, receptors occur outside synapses and can be activated by glutamate spillover, this principle may underlie synaptic homeostasis. Wong et al. (2004) responded to the comments by Rusakov et al. (2004) by stating that although they agreed that activation of extrasynaptic NR2B receptors by glutamate spillover may lead to heterosynaptic long-term depression, the data also supported a role of synaptic NR2B receptors in homosynaptic long-term depression. The proposed role of extrasynaptic NMDA receptor-mediated long-term depression in synaptic homeostasis may thus be temporally limited.
By examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, Popescu et al. (2004) showed that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predicted that, after binding neurotransmitter, receptors hesitate for approximately 4 milliseconds in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initial fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on the pulse frequency.
Among 304 Swiss individuals tested and genotyped, de Quervain and Papassotiropoulos (2006) found a significant association (p = 0.00008) between short-term episodic memory performance and genetic variations in a 7-gene cluster consisting of the ADCY8 (103070), PRKACG (176893), CAMK2G (602123), GRIN2A, GRIN2B, GRM3 (601115), and PRKCA (176960) genes, all of which have well-established molecular and biologic functions in animal memory. Functional MRI studies in an independent set of 32 individuals with similar memory performance showed a correlation between activation in memory-related brain regions, including the hippocampus and parahippocampal gyrus, and genetic variability in the 7-gene cluster. De Quervain and Papassotiropoulos (2006) concluded that these 7 genes encode proteins of the memory formation signaling cascade that are important for human memory function.
Micu et al. (2006) showed that NMDA glutamate receptors mediate calcium ion accumulation in central myelin in response to chemical ischemia in vitro. Using 2-photon microscopy, they imaged fluorescence of the calcium ion indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA/kainate receptor antagonist NBQX completely blocked the ischemic calcium ion increase in oligodendroglial cell bodies, but only modestly reduced the calcium ion increase in myelin. In contrast, the calcium ion increase in myelin was abolished by broad-spectrum NMDA receptor antagonists, but not by more selective blockers of NR2A and NR2B subunit-containing receptors. In vitro ischemia causes ultrastructural damage to both axon cylinders and myelin. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2, and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits were present for the formation of functional NMDA receptors. Micu et al. (2006) concluded that their data showed that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate, the finding that the calcium ion increase is mediated in large part by activation of myelinic NMDA receptors suggested a new mechanism of axomyelinic signaling.
In rodent cerebral cortex, there is a developmental switch from Nr2b- to Nr2a-containing NMDA receptors that is driven by activity and sensory experience. This subunit switch alters NMDA receptor function and influences synaptic plasticity. Using whole-cell patch-clamp recordings from CA1 pyramidal neurons of neonatal rats and Glur5 (GRIK1; 138245)-knockout mice, Matta et al. (2011) found that the Nr2b-to-Nr2a switch was rapid and required Glur5 in addition to NMDA receptor activation. Glutamate binding to Glur5 led to activation of PLC (see 607120), followed by release of calcium from intracellular stores and activation of PKC by diacylglycerol. A similar Nr2b-to-Nr2a switch requiring Glur5 occurred following visual stimulation at inputs onto layer 2/3 pyramidal neurons in mouse primary visual cortex.
Yan et al. (2020) found that the NMDAR subunits Grin2a and Grin2b formed a complex with Trpm4 (606936) in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that Yan et al. (2020) identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration.
Crystal Structure
Furukawa et al. (2005) reported the crystal structure of the ligand-binding core of NR2A with glutamate and that of the NR1 (GRIN1; 138249)-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defined the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggested a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiologic experiments, confirmed that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyr535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.
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.
Cryoelectron Microscopy
Lu et al. (2017) reported structures of the triheteromeric GluN1 (GRIN1)/GluN2A (GRIN2A)/GluN2B (GRIN2B; 138252) receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt 'closed' and 'open' clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold-related GluN1 subunits further reflect receptor asymmetry. Lu et al. (2017) concluded that the triheteromeric NMDAR structures provided the first view of the most common NMDA receptor assembly and showed how incorporation of 2 different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.
Reutlinger et al. (2010) reported 3 unrelated patients with different deletions of chromosome 16p13 including the GRIN2A gene who had early-onset focal epilepsy, severe intellectual disability, and lack of speech or delayed speech development (245570). EEG available from 2 patients showed centrotemporal spikes, reminiscent of Rolandic epilepsy, and electrical status epilepticus in sleep (ESES). All showed delayed global development from birth or early infancy. All had variable dysmorphic features, including low-set ears, epicanthal folds, hypertelorism, deep-set eyes, broad nasal tip, short nose, and brachydactyly. Genomewide screening for structural genomic variants identified 3 different deletions, ranging in size from 980 kb to 2.6 Mb, in the 3 patients. Two of the deletions were confirmed to be de novo; parental samples from the third patient were unavailable. The only gene located in the critical shared region of all 3 patients was GRIN2A.
Focal Epilepsy and Speech Disorder with or without Mental Retardation
Heterozygous germline mutations in the GRIN2A gene have been found in focal epilepsy with speech disorder (FESD; 245570), a childhood-onset seizure disorder with a highly variable phenotype. FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by Lesca et al., 2013; Lemke et al., 2013; Carvill et al., 2013).
In 3 members of a German family with childhood onset of focal seizures associated with variable learning difficulties and mental retardation (245570), Endele et al. (2010) identified a heterozygous mutation in the GRIN2A gene (Q218X; 138253.0001). Another heterozygous de novo mutation (N615K; 138253.0002) was found in a 3-year-old French girl with severe mental retardation and early-onset epileptic spasms and myoclonic seizures. The 2 mutations had a frequency of 1 in 254 alleles from 127 patients with a history of epilepsy and/or abnormal EEG and variable degrees of mental retardation. These findings suggested that the GRIN2A gene is important for proper neuronal activity and development. Endele et al. (2010) suggested that GRIN2A mutations may lead to abnormal subunit function and affect neuronal ion flux and electrical transmission between neurons, resulting in developmental abnormalities.
By sequence analysis of the GRIN2A gene in 519 probands with a range of epileptic encephalopathies, Carvill et al. (2013) identified heterozygous mutations (138253.0005-138253.0007) in 4 probands, all of whom came from the cohort of 44 patients with epilepsy-aphasia syndromes (9% of probands with epilepsy-aphasia syndromes). One of the probands was from the family reported by Scheffer et al. (1995) with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia; a heterozygous splice site mutation (138253.0005) segregated with the disorder in all 7 patients in this family. Two affected members of an unrelated family with epileptic encephalopathy with continuous spike and wave in slow-wave sleep (CSWS) also carried this mutation. Both were Australian families of European descent, and haplotype analysis indicated a founder effect. Three sibs from another family with CSWS or intermediate epilepsy-aphasia disorder carried a different heterozygous mutation (138253.0007). The fourth family with a GRIN2A mutation was diagnosed with Landau-Kleffner syndrome (LKS). The findings indicated that GRIN2A mutations can be associated with a wide range of epilepsy-aphasia spectrum phenotypes. No GRIN2A mutations were found in 475 patients with other epileptic encephalopathy phenotypes or in 81 patients with benign epilepsy with centrotemporal spikes (BECTS).
Lesca et al. (2013) examined the role of the GRIN2A gene in 66 probands with LKS or CSWS. Heterozygous inherited or de novo mutations (see, e.g., 138253.0008-138253.0010) were found in 7 of 7 families and in 6 of 59 patients with sporadic disease. Segregation studies in the families showed that some mutation carriers had atypical rolandic epilepsy. Two mutation carriers reportedly had benign childhood epilepsy. Most mutation carriers had dysphasia or verbal dyspraxia. Some mutation carriers were unaffected, indicating incomplete penetrance. Heterozygous GRIN2A mutations were subsequently found in 2 families with atypical rolandic epilepsy. One family with a mutation in the SRPX2 gene (300642.0001; Roll et al., 2006; 300643) also carried a heterozygous GRIN2A mutation. In total, 14 point mutations and 2 small deletions involving the GRIN2A gene (15 kb and 75 kb, respectively) were identified. Functional studies showed that 2 of the missense mutations caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current. GRIN2A mutations were located in different domains of the protein, and there were no apparent genotype/phenotype correlations. Lesca et al. (2013) concluded that GRIN2A mutations represent a major genetic determinant of LKS and CSWS, as well as related epileptic disorders in the same clinical continuum, such as atypical rolandic epilepsy and speech impairment.
Lemke et al. (2013) identified heterozygous mutations in the GRIN2A gene (see, e.g., 138253.0005; 138253.0011-138253.0012) in 27 (7.5%) of 359 patients from 2 independent cohorts with idiopathic focal epilepsy syndromes, including Landau-Kleffner syndrome, CSWS, atypical rolandic epilepsy, and benign epilepsy of childhood with centrotemporal spikes. Mutations occurred at a significantly higher frequency in patients compared to the Exome Variant Server (0.6%; p = 4.83 x 10(-18)) or in controls of European ancestry (p = 1.18 x 10(-16)). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12 (4.9%) of 245 individuals with BECTS to 9 (17.6%) of 51 with LKS/CSWS. Splice site, truncating, and frameshift mutations were more commonly associated with the more severe phenotypes, and missense mutations were more commonly associated with the more benign phenotypes. Segregation status was available for 18 families. The mutations segregated with a phenotype of different epileptic disorders within the families, ranging from BECTS to learning disabilities and intellectual disability to atypical rolandic epilepsy and CSWS; some mutations carriers were unaffected. Exon-disrupting microdeletions of the GRIN2A gene were also found in 3 (1%) of 286 individuals screened for copy number variations. The findings indicated that alterations of the GRIN2A gene are a major genetic risk factor for various types of idiopathic focal epilepsy.
Variant Function
Swanger et al. (2016) assessed variation across GRIN2A and GRIN2B (138252) domains and determined that the agonist-binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist-binding domain of GRIN2B exhibited significantly more variation intolerance than that of GRIN2A. To understand the ramifications of missense variation in the agonist-binding domain, Swanger et al. (2016) investigated the mechanisms by which 25 rare variants in the GRIN2A and GRIN2B agonist-binding domains dysregulated NMDA receptor activity. When introduced into recombinant human NMDA receptors, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. The approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and nonsynaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GRIN2A were associated with epilepsy, whereas GRIN2B variants were associated with intellectual disability with or without seizures.
Somatic Mutations in Melanoma
Using exome sequencing, Wei et al. (2011) found somatic mutations in the GRIN2A gene in 6 of 14 melanoma (155600) samples. A further 11 somatic mutations were found in a prevalence screen of 38 additional melanomas, and the findings were validated in 2 more panel sets. Overall, there were 34 distinct GRIN2A mutations in 135 melanoma samples (25.2%). These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including GRIN2A, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Sakimura et al. (1995) showed that targeted disruption of the mouse Nmdar2a gene produced mice that were viable, although impaired hippocampal plasticity was observed in homozygous -/- mice. By gene targeting, Sprengel et al. (1998) generated mutant mice expressing the Nmdar2a gene without the large intracellular C-terminal domain. These mice were viable but exhibited impaired synaptic plasticity and contextual memory. The authors concluded that the observed phenotypes appear to reflect defective intracellular signaling.
In both mice and humans, DeGiorgio et al. (2001) found that a subset of antibodies against double-stranded DNA (dsDNA) found in systemic lupus erythematosus (SLE; 152700) recognized portions of the extracellular domain of the NR2A and NR2B subunits, which are found in the hippocampus, amygdala, and hypothalamus. Huerta et al. (2006) showed that mice immunized to produce anti-dsDNA/anti-N2R IgG antibodies developed damage to neurons in the amygdala after being given epinephrine to induce leaks in the blood-brain barrier. The resulting neuronal insults were noninflammatory. Mice with antibody-mediated damage in the amygdala developed behavioral changes characterized by a deficient response to fear-conditioning paradigms. Huerta et al. (2006) postulated that when the blood-brain barrier is compromised, neurotoxic antibodies can penetrate the central nervous system and result in cognitive, emotional, and behavioral changes, as seen in neuropsychiatric lupus.
In 3 members of a German family with childhood seizures and variable neurodevelopmental defects ranging from mental retardation to learning difficulties (FESD; 245570), Endele et al. (2010) identified a heterozygous 652C-T transition in exon 4 of the GRIN2A gene, resulting in a gln218-to-ter (Q218X) substitution. The mutation was not found in 360 control chromosomes, and the mutant transcript was degraded by nonsense-mediated mRNA decay. These findings indicated loss of function.
In a 3-year-old French girl early-onset epileptic spasms and myoclonic seizures and severe mental retardation (FESD; 245570), Endele et al. (2010) identified a de novo heterozygous 1845C-A transversion in exon 10 of the GRIN2A gene, resulting in an asn615-to-lys (N615K) substitution in a conserved residue of the membrane reentrant loop (P-loop). The mutation was not found in 1,080 control chromosomes. In vitro functional expression studies showed that the mutant receptor had decreased calcium permeability. Moreover, coexpression with the wildtype protein showed a dominant-negative effect.
In a patient with severe intellectual disability, dysplastic corpus callosum, myelination delay, epilepsy, severe feeding problems, hypothyroidism, and mild facial dysmorphism (FESD; 245570), de Ligt et al. (2012) identified a de novo heterozygous 1945C-G transversion in the GRIN2A gene, resulting in a leu649-to-val (L649V) substitution. Functional studies were not performed.
In a patient with severe intellectual disability, no speech, epilepsy since 9 months of age, and spasticity (FESD; 245570), de Ligt et al. (2012) identified a de novo heterozygous 1655C-G transversion in the GRIN2A gene, resulting in a pro522-to-arg (P522R) substitution. Functional studies were not performed.
In affected members of a family with autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (FESD; 245570), originally reported by Scheffer et al. (1995), Carvill et al. (2013) identified a heterozygous G-to-A transition in intron 4 of the GRIN2A gene (c.1007+1G-A), predicted to result in the skipping of exon 4 and premature termination (Phe139IlefsTer15). The mutation was not found in 6,500 control exomes. The same heterozygous mutation was also found in a father and son with epileptic encephalopathy with continuous spike and wave in slow-wave sleep. Analysis of patient cells showed that the mutant transcript underwent nonsense-mediate mRNA decay. Both of the families were of European descent, and haplotype analysis indicated a founder effect. The findings suggested that GRIN2A mutations can cause a spectrum of epilepsy-aphasia phenotypes.
Lemke et al. (2013) identified a heterozygous c.1007+1G-A in 7 affected individuals from 3 unrelated families and in a singleton individual, all with variable manifestations of epilepsy, including Landau-Kleffner syndrome, continuous spike and waves during slow-wave sleep, atypical benign partial epilepsy, and benign epilepsy with centrotemporal spikes. Lemke et al. (2013) suggested that additional modifying factors might explain the phenotypic variability.
In 2 sisters with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of Landau-Kleffner syndrome, Carvill et al. (2013) identified a heterozygous c.2T-C transition in the GRIN2A gene, resulting in a met1-to-thr (M1T) substitution. The mutation was predicted to have detrimental effects on protein synthesis, but RNA was not available. Their father, who had unclassified epilepsy and speech/language disorder, also carried the mutation. The mutation was not found in 6,500 control exomes.
In 3 sibs with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of epilepsy-aphasia disorder or continuous spike and waves during slow-wave sleep syndrome, Carvill et al. (2013) identified a heterozygous c.1592C-T transition in the GRIN2A gene, resulting in a thr531-to-met (T531M) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in 6,500 control exomes. Coexpression of the mutant protein with wildtype GRIN1 (138249) in COS-7 cells resulted in a shift in NMDA receptor kinetics, with a 4-fold increase in the mean duration of the open state compared to wildtype channels. The patients had onset between ages 6.5 and 11 years of focal dyscognitive or tonic-clonic seizures that remitted in 2 patients by age 11 years. The patients had variably delayed development, mild intellectual disability, and speech/language difficulties. EEG findings were all abnormal and differed slightly, including centrotemporal spikes, high-voltage discharges while awake, and continuous spike-waves during sleep.
In affected members of a 3-generation family with variable expression of focal epilepsy and speech disorder (FESD; 245570), including clinical diagnoses of continuous spike and waves during slow-wave sleep (CSWS), Landau-Kleffner syndrome, and atypical rolandic epilepsy, Lesca et al. (2013) identified a heterozygous A-to-G transition in intron 5 of the GRIN2A gene (c.1123-2A-G), resulting in the skipping of exon 5 and premature termination (Val375fsTer). One mutation carrier was unaffected, suggesting incomplete penetrance. The findings were consistent with haploinsufficiency as the pathogenic effect. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In a patient with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lesca et al. (2013) identified a heterozygous c.1553G-A transition in the GRIN2A gene, resulting in an arg518-to-his (R518H) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes, or Exome Variant Server databases. The mutation was also present in the patient's brother, who had atypical rolandic epilepsy with dysphasia, and the father, who had verbal dyspraxia but no seizures. Another sib of the proband, who did not carry the mutation, had centrotemporal spikes on EEG without seizures, thus representing a phenocopy. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current.
In a patient with focal epilepsy and speech disorder (FESD; 245570) and autistic features, with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lesca et al. (2013) identified a de novo heterozygous c.1954T-G transversion in the GRIN2A gene, resulting in a phe652-to-val (F652V) substitution at a highly conserved residue in the extracellular ligand-binding domain. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. In vitro functional expression studies in HEK293 cells showed that the mutation caused a significant increase in the open time and a decrease in the closed time of NMDA channels compared to wildtype, consistent with a modulatory effect on the excitatory postsynaptic current.
In a patient with focal epilepsy and speech disorder (FESD; 245570), with the clinical diagnosis of Landau-Kleffner syndrome, Lemke et al. (2013) identified a heterozygous c.2941C-T transition in the GRIN2A gene, resulting in an arg681-to-ter (R681X) substitution. The patient had a learning disability and language disorder. Family history showed that 2 relatives with learning disabilities also carried the mutation, as did an unaffected individual.
In a patient with focal epilepsy and speech disorder with mental retardation (FESD; 245570), with the clinical diagnosis of continuous spike and waves during slow-wave sleep syndrome, Lemke et al. (2013) identified a heterozygous c.2829C-G transversion in the GRIN2A gene, resulting in a tyr943-to-ter (Y943X) substitution. The mutation was also found in the patient's sib, who had febrile seizures and centrotemporal spikes on EEG, and in the patient's father, who had benign epilepsy of childhood with centrotemporal spikes.
Carvill, G. L., Regan, B. M., Yendle, S. C., O'Roak, B. J., Lozovaya, N., Bruneau, N., Burnashev, N., Khan, A., Cook, J., Geraghty, E., Sadleir, L. G., Turner, S. J., and 10 others. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nature Genet. 45: 1073-1076, 2013. [PubMed: 23933818] [Full Text: https://doi.org/10.1038/ng.2727]
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