Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes

Nat Genet. 2010 Nov;42(11):1021-6. doi: 10.1038/ng.677. Epub 2010 Oct 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • NR2B NMDA receptor
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Magnesium
  • Calcium
  • N-methyl D-aspartate receptor subtype 2A