Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortüm F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Tönnies H et al. (2010): Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes
Nat. Genet. 42: 1021-1026. Epub Oct 3. doi:10.1038/ng.677.

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.