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Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes 总被引:1,自引:0,他引:1
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 Villeneuve N Villard L Zabel B Zenker M Laube B Reis A Wieczorek D Van Maldergem L Kutsche K 《Nature genetics》2010,42(11):1021-1026
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. 相似文献
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