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

Akane Yoshikawa,Yosuke Eriguchi,Kayoko Kato,Aya Inai,Tsukasa Sasaki,Fumichika Nishimura,Chihiro Kakiuchi,Atsuhiko Takaya,Mamoru Tochigi,Masaki Nishioka,Yoshiya Kawamura,Kiyoto Kasai,Tadashi Umekage

doi:10.1038/hgv.2017.56

Abstract

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.

Highlights

The onset of schizophrenia (SCZ) usually occurs during early adolescence
We performed target re-sequencing of cyclin-dependent kinase 5 (CDK5), CSNK2A1, and EphB2, genes that are shown to regulate the N-methyl-D-aspartate receptors (NMDARs) switch via phosphorylation of NR2B Y1472 or S1480, in patients with SCZ and controls
To examine whether the developmental NMDAR subunit switch was genetically involved in the pathophysiology of SCZ, we performed target re-sequencing of CDK5, CSNK2A1, and EphB2, that regulate developmental NMDAR subunit switch via phosphorylation of NR2B Y1472 or S1480, using samples from patients with SCZ and controls

Summary

Introduction

The onset of schizophrenia (SCZ) usually occurs during early adolescence. SCZ is a neurodevelopmental disorder with a strong genetic component and is highly related to disturbances in brain/ circuit maturation.[1,2,3] the molecular mechanisms underlying the vulnerability for SCZ during early adolescence remain elusive. N-methyl-D-aspartate receptors (NMDARs) is involved in the pathophysiology of SCZ.[4,5,6,7,8,9,10,11] This hypothesis was initially based on clinical findings that the uncompetitive NMDAR antagonists, phencyclidine (PCP) and ketamine, induced psychotic features resembling symptoms seen in patients with SCZ. These features included both positive and negative symptoms, as well as cognitive dysfunction in healthy volunteers.[5] In addition, PCP exacerbated these symptoms in patients with chronic SCZ.[12]

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Results

Conclusion