Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors 
cause variable neurodevelopmental phenotypes

Endele, S.; Rosenberger, G.; Geider, K.; Popp, B.; Tamer, C.; Stefanova, I.; Milh, M.; Kortum, F.; Fritsch, A.; Pientka, F. K.; Hellenbroich, Y.; Kalscheuer, V. M.; Kohlhase, J.; Moog, U.; Rappold, G.; Rauch, A.; Ropers, H. H.; von Spiczak, S.; Tonnies, H.; Villeneuve, N.; Villard, L.; Zabel, B.; Zenker, M.; Laube, B.; Reis, A.; Wieczorek, D.; Van Maldergem, L.; Kutsche, K.

doi:10.1038/ng.677

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Journal Article

Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

MPS-Authors

Endele, S.
Max Planck Society;

Rosenberger, G.
Max Planck Society;

Geider, K.
Max Planck Society;

Popp, B.
Max Planck Society;

Tamer, C.
Max Planck Society;

Stefanova, I.
Max Planck Society;

Milh, M.
Max Planck Society;

Kortum, F.
Max Planck Society;

Fritsch, A.
Max Planck Society;

Pientka, F. K.
Max Planck Society;

Hellenbroich, Y.
Max Planck Society;

Kalscheuer, V. M.
Max Planck Society;

Kohlhase, J.
Max Planck Society;

Moog, U.
Max Planck Society;

Rappold, G.
Max Planck Society;

Rauch, A.
Max Planck Society;

Ropers, H. H.
Max Planck Society;

von Spiczak, S.
Max Planck Society;

Tonnies, H.
Max Planck Society;

Villeneuve, N.
Max Planck Society;

Villard, L.
Max Planck Society;

Zabel, B.
Max Planck Society;

Zenker, M.
Max Planck Society;

Laube, B.
Max Planck Society;

Reis, A.
Max Planck Society;

Wieczorek, D.
Max Planck Society;

Van Maldergem, L.
Max Planck Society;

Kutsche, K.
Max Planck Society;

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http://www.ncbi.nlm.nih.gov/pubmed/20890276
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Citation

Endele, S., Rosenberger, G., Geider, K., Popp, B., Tamer, C., Stefanova, I., et al. (2010). Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet, 42(11), 1021-6. doi:10.1038/ng.677.

Cite as: https://hdl.handle.net/21.11116/0000-0002-E031-9

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 Ca(2)(+)-permeable cation channels which are blocked by extracellular Mg(2)(+) in a voltage-dependent manner. 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-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg(2)(+) block and a decrease in Ca(2)(+) 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.