ArticleAnnals of neurology2014
GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy.
Article in Annals of neurology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers, 1 of them a synthesis that pooled it.
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Who cites it
115 citing papers in PubMed, 1 synthesis or guideline pooled it, 210 citations in OpenAlex.
- Customized multigene panels in epilepsy: the best things come in small packages.Neurogenetics · 2020Pooled it
- Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.PloS one · 2016Trial
- Hypoxia-inducible factor signaling regulates embryonic interneuron development, GRIN2B expression and adult cortical function.Developmental cell · 2026Article
- Absence seizures and sleep-wake abnormalities in a rat model of GRIN2B neurodevelopmental disorder.Epilepsia · 2025Article
- Diverse species of animal models in epilepsy research: Progress and perspectives.Zoological research · 2025Review
- GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications.Orphanet journal of rare diseases · 2025Article
- GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains.The Journal of general physiology · 2025Article
- Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes.Cell reports · 2025Article
- Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.Human molecular genetics · 2025Article
- Ligand distances as key predictors of pathogenicity and function in NMDA receptors.Human molecular genetics · 2025Article
- The NMDAR-BK channelosomes as regulators of synaptic plasticity.Biochemical Society transactions · 2025Review
- Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.Biomolecules · 2025Review
- Reduction of the CaFrontiers in cellular neuroscience · 2025Review
- Mechanisms of Action Underlying Conductance-Modifying Positive Allosteric Modulators of the NMDA Receptor.Molecular pharmacology · 2024Article
- Anterior cingulate cortex-related functional hyperconnectivity underlies sensory hypersensitivity in Grin2b-mutant mice.Molecular psychiatry · 2024Article
- Article
- 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
- Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine.Genes · 2024Review
- Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.Neural regeneration research · 2023Article
55 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 14 institutions in 5 countries.
Funding
Abstract
objectiveTo identify novel epilepsy genes using a panel approach and describe the functional consequences of mutations.
methodsUsing a panel approach, we screened 357 patients comprising a vast spectrum of epileptic disorders for defects in genes known to contribute to epilepsy and/or intellectual disability (ID). After detection of mutations in a novel epilepsy gene, we investigated functional effects in Xenopus laevis oocytes and screened a follow-up cohort.
resultsWe revealed de novo mutations in GRIN2B encoding the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in 2 individuals with West syndrome and severe developmental delay as well as 1 individual with ID and focal epilepsy. The patient with ID and focal epilepsy had a missense mutation in the extracellular glutamate-binding domain (p.Arg540His), whereas both West syndrome patients carried missense mutations within the NR2B ion channel-forming re-entrant loop (p.Asn615Ile, p.Val618Gly). Subsequent screening of 47 patients with unexplained infantile spasms did not reveal additional de novo mutations, but detected a carrier of a novel inherited GRIN2B splice site variant in close proximity (c.2011-5_2011-4delTC). Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx, whereas p.Arg540His caused less severe disturbance of channel function, corresponding to the milder patient phenotype.
interpretationWe identified GRIN2B gain-of-function mutations as a cause of West syndrome with severe developmental delay as well as of ID with childhood onset focal epilepsy. Severely disturbed channel function corresponded to severe clinical phenotypes, underlining the important role of facilitated NMDA receptor signaling in epileptogenesis.
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