Miyatake R, Furukawa A, Suwaki H
Department of Neuropsychiatry, Faculty of Medicine, Kagawa Medical University, Kagawa, Japan.
Mol Psychiatry. 2002;7(10):1101-6. doi: 10.1038/sj.mp.4001152.
N-methyl-D-aspartate (NMDA) receptor dysfunction is involved in the pathogenesis of schizophrenia. We determined the nucleotide sequence of the 5'-upstream region of the human NMDA receptor 2B (NR2B) subunit gene and identified a novel T-200G variant located in one of the Sp1 binding sites. To investigate the effect of this variant on the transcriptional activity of the hNR2B gene, we performed gene reporter assays using PC12 pheochromocytoma cells transiently transfected with luciferase reporter plasmids. In the absence of nerve growth factor (NGF), luciferase activities did not significantly differ between the two alleles and the control plasmid. However, luciferase reporter activity of the T allele was significantly up-regulated compared to that of the G allele in the presence of NGF (P = 0.0013), indicating that this polymorphic site is a critical region for NR2B gene regulation through NGF-induced Sp1-binding. A case control study showed that the frequency of the G allele (P = 0.0164) was significantly higher in 100 schizophrenics than in 100 controls. These findings suggest that the T-200G variant causes dysfunction of NMDA receptors consisting of the NR2B subunit and may be involved in the development of schizophrenia. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings.
N-甲基-D-天冬氨酸（NMDA）受体功能障碍与精神分裂症的发病机制有关。我们测定了人类NMDA受体2B（NR2B）亚基基因5'-上游区域的核苷酸序列，并鉴定出一个位于Sp1结合位点之一的新型T-200G变异。为了研究该变异对hNR2B基因转录活性的影响，我们使用瞬时转染荧光素酶报告质粒的PC12嗜铬细胞瘤细胞进行了基因报告分析。在没有神经生长因子（NGF）的情况下，两个等位基因与对照质粒之间的荧光素酶活性没有显著差异。然而，在存在NGF的情况下，T等位基因的荧光素酶报告活性与G等位基因相比显著上调（P = 0.0013），表明该多态性位点是通过NGF诱导的Sp1结合来调节NR2B基因的关键区域。一项病例对照研究表明，在100名精神分裂症患者中G等位基因的频率（P = 0.0164）显著高于100名对照。这些发现表明，T-200G变异导致由NR2B亚基组成的NMDA受体功能障碍，并可能参与精神分裂症的发生发展。需要对独立样本进行重复研究和基于家系的关联研究，以进一步评估我们发现的意义。
