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  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., 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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-E031-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-E032-8
Genre: Journal Article

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 Creators:
Endele, S.1, Author
Rosenberger, G.1, Author
Geider, K.1, Author
Popp, B.1, Author
Tamer, C.1, Author
Stefanova, I.1, Author
Milh, M.1, Author
Kortum, F.1, Author
Fritsch, A.1, Author
Pientka, F. K.1, Author
Hellenbroich, Y.1, Author
Kalscheuer, V. M.1, Author
Kohlhase, J.1, Author
Moog, U.1, Author
Rappold, G.1, Author
Rauch, A.1, Author
Ropers, H. H.1, Author
von Spiczak, S.1, Author
Tonnies, H.1, Author
Villeneuve, N.1, Author
Villard, L.1, AuthorZabel, B.1, AuthorZenker, M.1, AuthorLaube, B.1, AuthorReis, A.1, AuthorWieczorek, D.1, AuthorVan Maldergem, L.1, AuthorKutsche, K.1, Author more..
Affiliations:
1Max Planck Society, ou_persistent13              

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Free keywords: Adolescent Adult Amino Acid Substitution Calcium/metabolism Child Child, Preschool Epilepsy/*genetics Female Humans Intellectual Disability/*genetics Magnesium/metabolism Male Mutation Nervous System Diseases/*genetics Pedigree *Polymorphism, Single Nucleotide Protein Subunits/genetics Receptors, N-Methyl-D-Aspartate/*genetics Transcription, Genetic
 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.

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 Dates: 2010
 Publication Status: Published in print
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 Identifiers: Other: 20890276
DOI: 10.1038/ng.677
ISSN: 1546-1718 (Electronic) 1061-4036 (Linking)
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Title: Nat Genet
  Alternative Title : Nature genetics
Source Genre: Journal
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Pages: - Volume / Issue: 42 (11) Sequence Number: - Start / End Page: 1021 - 6 Identifier: -