Abstract
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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Acknowledgements
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).
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Mutation analysis: S.E., B.P. and G. Rosenberger. Transcript analysis: K.K. and G. Rosenberger. Functional analysis of NMDA receptors: K.G. and B.L. NMDA receptor modeling: C.T. and B.L. Subject ascertainment: Y.H., L.V.M., M.M., U.M., G. Rappold, A. Rauch, S.v.S., I.S., N.V., L.V., D.W., B.Z. and M.Z. FISH analysis and breakpoint mapping: A.F., V.M.K., F.K., F.K.P. and H.-H.R. Array CGH analysis: J.K. and H.T. Manuscript writing: K.K., V.M.K., B.L., L.V.M., A. Reis, G. Rosenberger and D.W. Study design: K.K., L.V.M., A. Reis, G. Rosenberger and D.W. All authors contributed to the final version of the paper.
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Endele, S., Rosenberger, G., Geider, K. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 42, 1021–1026 (2010). https://doi.org/10.1038/ng.677
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DOI: https://doi.org/10.1038/ng.677
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