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

Endele, Sabine and Rosenberger, Georg and Geider, Kirsten and Popp, Bernt and Tamer, Ceyhun and Stefanova, Irina and Milh, Mathieu and Kortüm, Fanny and Fritsch, Angela and Pientka, Friederike K. and Hellenbroich, Yorck and Kalscheuer, Vera M. and Kohlhase, Jürgen and Moog, Ute and Rappold, Gudrun and Rauch, Anita and Ropers, Hans-Hilger and von Spiczak, Sarah and Tönnies, Holger and Villeneuve, Nathalie and Villard, Laurent and Zabel, Bernhard and Zenker, Martin and Laube, Bodo and Reis, André and Wieczorek, Dagmar and Van Maldergem, Lionel and Kutsche, Kerstin :
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
In: Nature genetics, 42 (11) pp. 1021-6. ISSN 1546-1718
[Article] , (2010)

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 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 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.

Item Type: Article
Erschienen: 2010
Creators: Endele, Sabine and Rosenberger, Georg and Geider, Kirsten and Popp, Bernt and Tamer, Ceyhun and Stefanova, Irina and Milh, Mathieu and Kortüm, Fanny and Fritsch, Angela and Pientka, Friederike K. and Hellenbroich, Yorck and Kalscheuer, Vera M. and Kohlhase, Jürgen and Moog, Ute and Rappold, Gudrun and Rauch, Anita and Ropers, Hans-Hilger and von Spiczak, Sarah and Tönnies, Holger and Villeneuve, Nathalie and Villard, Laurent and Zabel, Bernhard and Zenker, Martin and Laube, Bodo and Reis, André and Wieczorek, Dagmar and Van Maldergem, Lionel and Kutsche, Kerstin
Title: Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Language: English
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 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 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.

Journal or Publication Title: Nature genetics
Volume: 42
Number: 11
Divisions: 10 Department of Biology
10 Department of Biology > Neurophysiology and Neurosensory Systems
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Date Deposited: 11 Apr 2011 09:11
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