Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia
Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia
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DOI：
10.1038/sj.mp.4001152
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发表时间：
2002-01-01
影响因子：
11
通讯作者：
Suwaki, H
中科院分区：
文献类型：
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作者：
Miyatake, R;Furukawa, A;Suwaki, H
N-甲基-D-天冬氨酸（NMDA）受体功能障碍参与精神分裂症的发病机制。我们确定了人NMDA受体2B（NR 2B）亚基基因5 '上游区域的核苷酸序列，并鉴定了位于Sp1结合位点之一的新型T-200 G变体。为了研究这种变体对hNR 2B基因转录活性的影响，我们使用荧光素酶报告质粒瞬时转染的PC 12嗜铬细胞瘤细胞进行了基因报告试验。在神经生长因子（NGF）的情况下，荧光素酶活性没有显着差异的两个等位基因和对照质粒。然而，荧光素酶报告活性的T等位基因的显着上调相比，G等位基因的存在下的神经生长因子（P = 0.0013），表明该多态性位点是一个关键区域，通过神经生长因子诱导的Sp1结合NR 2B基因调控。病例对照研究表明，100例精神分裂症患者G等位基因频率（P = 0.0164）显著高于100例对照组。这些发现表明，T-200 G变异体引起由NR 2B亚基组成的NMDA受体功能障碍，并可能参与精神分裂症的发展。独立样本的重复研究和以家庭为基础的关联研究是必要的，以进一步评估我们的研究结果的意义。
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.