ArticleNature communications2014
Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy.
Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 143 citations in OpenAlex.
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- Inhibition of GluN2B-containing N-methyl-D-aspartate receptors by radiprodil.Brain : a journal of neurology · 2026Article
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- Stimulus-Transcription Coupling of TRPM3 Channels: A Signaling Pathway from the Plasma Membrane to the Nucleus.Biomolecules · 2025Review
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- Comprehensive Gene Expression Analysis Using Human Induced Pluripotent Stem Cells Derived from Patients with Sleep Bruxism: A Preliminary In Vitro Study.International journal of molecular sciences · 2024Article
- Clinical phenotype and functional influence of GRIN2A variants in epilepsy-aphasia syndrome.Epilepsia open · 2024Article
- Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.Physiological research · 2024Review
- Rescuing tri-heteromeric NMDA receptor function: the potential of pregnenolone-sulfate in loss-of-function GRIN2B variants.Cellular and molecular life sciences : CMLS · 2024Article
- De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.Cellular and molecular life sciences : CMLS · 2024Article
- Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders.Scientific reports · 2024Article
- Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.Human molecular genetics · 2024Article
- Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants.Acta pharmacologica Sinica · 2024Article
- Selective Cell-Surface Expression of Triheteromeric NMDA Receptors.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Excitation/Inhibition balance relates to cognitive function and gene expression in temporal lobe epilepsy: a high density EEG assessment with aperiodic exponent.Brain communications · 2024Article
- Article
- An integrated approach to evaluate the functional effects of disease-associated NMDA receptor variants.Neuropharmacology · 2023Article
- Clinical and functional consequences of GRIA variants in patients with neurological diseases.Cellular and molecular life sciences : CMLS · 2023Article
- Classification of missense variants in the N-methyl-d-aspartate receptor GRIN gene family as gain- or loss-of-function.Human molecular genetics · 2023Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.
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