Ohtsuki Tsuyuka, Koga Minori, Ishiguro Hiroki, Horiuchi Yasue, Arai Makoto, Niizato Kazuhiro, Itokawa Masanari, Inada Toshiya, Iwata Nakao, Iritani Shyuji, Ozaki Norio, Kunugi Hiroshi, Ujike Hiroshi, Watanabe Yuichiro, Someya Toshiuki, Arinami Tadao
Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Schizophr Res. 2008 Apr;101(1-3):9-16. doi: 10.1016/j.schres.2008.01.027. Epub 2008 Mar 10.
Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia.
We screened for mutations in all exons, exon/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual-luciferase assay in transfected cells.
Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p=0.009). Dual-luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles.
Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia.
谷氨酸功能障碍与精神分裂症的病理生理学有关。代谢型谷氨酸受体（mGluRs）是G蛋白偶联受体。GRM7是编码mGluR7的基因，在人类中枢神经系统的许多区域表达。GRM7基因位于人类3号染色体p26上，连锁分析表明该区域含有精神分裂症的易感基因座。
我们对日本精神分裂症患者GRM7基因的所有外显子、外显子/内含子连接区和启动子区域进行突变筛查，并评估检测到的多态性与精神分裂症之间的关联。我们通过转染细胞中的双荧光素酶测定法研究了一种与精神分裂症相关的多态性对GRM7表达的影响。
在GRM7中检测到25种多态性/突变。病例对照分析显示，在我们对2293名日本精神分裂症患者和2382名日本对照受试者的病例对照研究中，外显子1中的同义多态性（371T/C，rs3749380）与精神分裂症存在潜在关联（等位基因p = 0.009）。双荧光素酶测定显示，含有这种多态性的外显子1抑制转录活性，并且T和C等位基因之间的启动子活性存在统计学显著差异。
我们的结果支持GRM7基因多态性与精神分裂症遗传易感性可能存在关联。
