title: Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
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.
authors.affiliation: Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
authors.forename: Georg
authors.initials: G
authors.lastname: Rosenberger
authors.forename: Kirsten
authors.initials: K
authors.lastname: Geider
authors.forename: Bernt
authors.initials: B
authors.lastname: Popp
authors.forename: Ceyhun
authors.initials: C
authors.lastname: Tamer
authors.forename: Irina
authors.initials: I
authors.lastname: Stefanova
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.forename: Fanny
authors.initials: F
authors.lastname: Kortüm
authors.forename: Angela
authors.initials: A
authors.lastname: Fritsch
authors.forename: Friederike K
authors.initials: FK
authors.lastname: Pientka
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Sarah
authors.initials: S
authors.lastname: von Spiczak
authors.forename: Holger
authors.initials: H
authors.lastname: Tönnies
authors.forename: Nathalie
authors.initials: N
authors.lastname: Villeneuve
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Bodo
authors.initials: B
authors.lastname: Laube
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008274:Magnesium / Q000378:metabolism; D008297:Male; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002118:Calcium; D008274:Magnesium; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor