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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.
