N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca2+-permeable cation channels which are blocked by extracellular Mg2+ in a voltage-dependent manner1. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2AN615K (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg2+ block and a decrease in Ca2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
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We thank all subjects and healthy (control) individuals for their participation in this study; P. De Jonghe for providing DNA samples of individuals with idiopathic epilepsy; A. Gal and B. Horsthemke for continuous support; H.-H. Richardt and H. Petri for clinical evaluation of subjects 3 and 1; A. Tzschach and M. Hoeltzenbein for initial help with collecting clinical data of subject 2; S. Fuchs for chromosome analysis; B. Lübker and C. Menzel for FISH analysis; R. Ullmann and A. Ahmed for array comparative genomic hybridization (CGH) on subject 2, O. Riess and M. Bonin for copy number variation analysis on subjects 8 and 9, and I. Göhring and A.B. Ekici for microarray analysis of the Erlanger cohort; S. Berkel, J. Hoyer and K. Cremer for support with data maintenance; and A. Diem, S. Freier, I. Jantke, S. Meien and K. Ziegler for skillfull technical assistance. This work was part of the German Mental Retardation Network (MRNET) funded through a grant from the German Ministry of Research and Education to A. Rauch and A. Reis (01GS08160), G. Rappold (01GS08168-9), H.-H.R. (01GS08161) and D.W. (01GS08164). M.M. was supported by the Fondation Française pour la Recherche sur l'Epilepsie, B.L. was supported by the Gemeinnützige Hertie-Stiftung, and G. Rosenberger and K.K. were supported by a grant from the Deutsche Forschungsgemeinschaft (FOR 885/IRP5).
The authors declare no competing financial interests.
About this article
Human Mutation (2019)
De novo GRIN variants in NMDA receptor M2 channel pore‐forming loop are associated with neurological diseases
Human Mutation (2019)
Clinical Genetics (2019)
Annals of Human Biology (2019)
Pharmacology & Therapeutics (2019)