Article (Scientific journals)
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Endele, Sabine; Rosenberger, Georg; Geider, Kirsten et al.
2010In Nature Genetics, 42 (11), p. 1021-6
Peer Reviewed verified by ORBi
 

Files


Full Text
Mutations in GRIN2A-5Van Maldergem.pdf
Publisher postprint (1.05 MB)
Request a copy

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
Adolescent; Adult; Amino Acid Substitution; Calcium/metabolism; Child; Child, Preschool; Epilepsy/genetics; Female; Humans; Magnesium/metabolism; Male; Mental Retardation/genetics; Mutation; Nervous System Diseases/genetics; Pedigree; Polymorphism, Single Nucleotide; Protein Subunits/genetics; Receptors, N-Methyl-D-Aspartate/genetics; Transcription, Genetic
Abstract :
[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Endele, Sabine
Rosenberger, Georg
Geider, Kirsten
Popp, Bernt
Tamer, Ceyhun
Stefanova, Irina
Milh, Mathieu
Kortum, Fanny
Fritsch, Angela
Pientka, Friederike K
Hellenbroich, Yorck
Kalscheuer, Vera M
Kohlhase, Jurgen
Moog, Ute
Rappold, Gudrun
Rauch, Anita
Ropers, Hans*-Hilger
von Spiczak, Sarah
Tonnies, Holger
Villeneuve, Nathalie
Villard, Laurent
Zabel, Bernhard
Zenker, Martin
Laube, Bodo
Reis, Andre
Wieczorek, Dagmar
Van Maldergem, Lionel ;  Centre Hospitalier Universitaire de Liège - CHU > Génétique
Kutsche, Kerstin
More authors (18 more) Less
Language :
English
Title :
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Publication date :
2010
Journal title :
Nature Genetics
ISSN :
1061-4036
eISSN :
1546-1718
Publisher :
Nature Publishing Group, New York, United States - New York
Volume :
42
Issue :
11
Pages :
1021-6
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 24 January 2011

Statistics


Number of views
70 (1 by ULiège)
Number of downloads
0 (0 by ULiège)

Scopus citations®
 
400
Scopus citations®
without self-citations
379
OpenCitations
 
366

Bibliography


Similar publications



Contact ORBi