ArticleBrain : a journal of neurology2018
De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.
Article in Brain : a journal of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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57 citing papers in PubMed, 99 citations in OpenAlex.
- GRIN-related epilepsy in Chinese pediatric patients: a retrospective study of clinical, genetic, and mutant protein structural features in a tertiary center cohort.World journal of pediatrics : WJP · 2026Article
- The Molecular Machinery of Synaptic Plasticity and Its Potential Role in the Aetiology of Schizophrenia.Molecular neurobiology · 2026Review
- Movement Disorders in Developmental and Epileptic Encephalopathies.Movement disorders clinical practice · 2026Review
- Neurodevelopmental disorder-causing GRIN1 Y647S variant alters red blood cell physiology in mice.Physiological reports · 2026Article
- Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant.iScience · 2026Article
- Rare dysfunctional SCN2A variants are associated with malformation of cortical development.Epilepsia · 2025Article
- Article
- GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.Molecular diversity · 2024Review
- Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.Physiological research · 2024Review
- De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.Cellular and molecular life sciences : CMLS · 2024Article
- Developmental loss of NMDA receptors results in supernumerary forebrain neurons through delayed maturation of transit-amplifying neuroblasts.Scientific reports · 2024Article
- The "microcephalic hydrocephalus" paradox as a paradigm of altered neural stem cell biology.Cerebral cortex (New York, N.Y. : 1991) · 2024Article
- Spectrum of NMDA Receptor Variants in Neurodevelopmental Disorders and Epilepsy.Methods in molecular biology (Clifton, N.J.) · 2024Review
- Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.Neural regeneration research · 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
- Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals.Nature communications · 2023Article
- Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the S688Y Mutation in the NMDA Receptor GluN1 Subunit.Molecules (Basel, Switzerland) · 2023Article
- Functional effects of disease-associated variants reveal that the S1-M1 linker of the NMDA receptor critically controls channel opening.Cellular and molecular life sciences : CMLS · 2023Article
- The phenotypic spectrum associated with loss-of-function variants in monogenic epilepsy genes in the general population.European journal of human genetics : EJHG · 2023Article
- Overlapping cortical malformations in patients with pathogenic variants inJournal of medical genetics · 2023Article
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41 authors at 20 institutions in 7 countries.
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Abstract
Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.
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