Yoshikawa Akane, Nishimura Fumichika, Inai Aya, Eriguchi Yosuke, Nishioka Masaki, Takaya Atsuhiko, Tochigi Mamoru, Kawamura Yoshiya, Umekage Tadashi, Kato Kayoko, Sasaki Tsukasa, Kasai Kiyoto, Kakiuchi Chihiro
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hum Genome Var. 2018 Feb 1;5:17056. doi: 10.1038/hgv.2017.56. eCollection 2018.
The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of -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 , , and 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 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 (=0.062). In silico analyses predicted P271T to be damaging. Further genetic research using a larger sample is required to examine whether is involved in the pathophysiology of SCZ.
青少年期易患精神分裂症（SCZ）的潜在机制仍不清楚。N-甲基-D-天冬氨酸受体（NMDARs）功能低下与SCZ的病理生理学有关。在发育过程中，突触NMDARs的组成通过细胞周期蛋白依赖性激酶5（CDK5）、酪蛋白激酶2α1（CSNK2A1）和EphB2对NR2B的S1480或Y1472进行磷酸化，从含NR2B的NMDARs显著转变为含NR2A的NMDARs，这在神经回路成熟中起关键作用。我们推测NMDARs发育变化的失调可能与SCZ的发病有关。使用下一代测序技术，我们对474例SCZ患者和475例健康对照者的、和的所有编码区和剪接位点进行了重新测序。去除了日本人群体对照数据库中的变异，并使用桑格测序法验证了所有非同义变异和无义变异。在SCZ患者中观察到了4个新的变异，但在对照者中未观察到。然而，SCZ组和对照组之间的变异总数没有显著差异（=0.062）。计算机分析预测P271T具有破坏性。需要使用更大样本进行进一步的遗传学研究，以检查是否参与SCZ的病理生理学。
