Novel rare variations in genes that regulate developmental change in N-methyl-d-aspartate receptor in patients with schizophrenia

The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of N -methyl- d -aspartate receptors (NMDARs) has been implicated in the pathophysiology of SCZ. During development, the composition of synaptic NMDARs dramatically changes from NR2B-containing NMDARs to NR2A-containing NMDARs through the phosphorylation of NR2B S1480 or Y1472 by CDK5, CSNK2A1, and EphB2, which plays a pivotal role in the maturation of neural circuits. We hypothesized that the dysregulation of developmental change in NMDARs could be involved in the onset of SCZ. Using next-generation sequencing, we re-sequenced all the coding regions and splice sites of CDK5 , CSNK2A1 , and EphB2 in 474 patients with SCZ and 475 healthy controls. Variants on the database for human control subjects of Japanese origin were removed and all the nonsynonymous and nonsense variants were validated using Sanger sequencing. Four novel variants in CDK5 were observed in patients with SCZ but were not observed in controls. The total number of variants, however, was not significantly different between the SCZ and control groups ( P =0.062). In silico analyses predicted P271T to be damaging. Further genetic research using a larger sample is required to examine whether CDK5 is involved in the pathophysiology of SCZ. Schizophrenia: Seeking genetic switches Mutations in genes that regulate development of key brain receptors may play a role in the onset of schizophrenia. In adolescence, genetic switches trigger reorganization of N-methyl-D-aspartate receptors (NMDAR), which are important in learning and memory. This reorganization is crucial for brain maturation. Schizophrenia often develops in adolescence, and accumulating evidence indicates that impaired NMDAR function may trigger its onset. Akane Yoshikawa at the University of Tokyo and co-workers sequenced the genes that trigger NMDAR reorganization in patients with schizophrenia and in healthy individuals. The researchers identified four mutations that were found in one of these genes in patients with schizophrenia but not in healthy controls. More data are needed to confirm the results. The researchers recommend further investigation of these genes in larger populations in hopes of identifying genetic changes underlying onset of schizophrenia.