Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
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.
Endele
Sabine
S
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Rosenberger
Georg
G
Geider
Kirsten
K
Popp
Bernt
B
Tamer
Ceyhun
C
Stefanova
Irina
I
Milh
Mathieu
M
Kortüm
Fanny
F
Fritsch
Angela
A
Pientka
Friederike K
FK
Hellenbroich
Yorck
Y
Kalscheuer
Vera M
VM
Kohlhase
Jürgen
J
Moog
Ute
U
Rappold
Gudrun
G
Rauch
Anita
A
Ropers
Hans-Hilger
HH
von Spiczak
Sarah
S
Tönnies
Holger
H
Villeneuve
Nathalie
N
Villard
Laurent
L
Zabel
Bernhard
B
Zenker
Martin
M
Laube
Bodo
B
Reis
André
A
Wieczorek
Dagmar
D
Van Maldergem
Lionel
L
Kutsche
Kerstin
K
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
D002118:Calcium; D008274:Magnesium; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor