Koga Minori, Ishiguro Hiroki, Yazaki Saori, Horiuchi Yasue, Arai Makoto, Niizato Kazuhiro, Iritani Shuji, Itokawa Masanari, Inada Toshiya, Iwata Nakao, Ozaki Norio, Ujike Hiroshi, Kunugi Hiroshi, Sasaki Tsukasa, Takahashi Makoto, Watanabe Yuichiro, Someya Toshiyuki, Kakita Akiyoshi, Takahashi Hitoshi, Nawa Hiroyuki, Muchardt Christian, Yaniv Moshe, Arinami Tadao
Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba,Tsukuba, Ibaraki, Japan.
Hum Mol Genet. 2009 Jul 1;18(13):2483-94. doi: 10.1093/hmg/ddp166. Epub 2009 Apr 10.
Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.
染色质重塑可能在精神分裂症的神经生物学中发挥作用，因此该过程可被视为一个治疗靶点。SMARCA2基因在SWI/SNF染色质重塑复合物中编码BRM，在对11883个单核苷酸多态性（SNP）进行筛查后，在日本人群的SMARCA2基因的两个连锁不平衡区域发现了SNP与精神分裂症的关联（rs2296212；总体等位基因P = 5.8×10⁻⁵），随后对22个参与染色质重塑的基因进行筛查（rs3793490；总体等位基因P = 2.0×10⁻⁶）。一个错义多态性（rs2296212）的风险等位基因导致BRM的核定位效率降低，内含子多态性（rs3763627和rs3793490）的风险等位基因与死后前额叶皮质中SMARCA2的低表达水平相关。在精神分裂症前额叶皮质（来自斯坦利医学研究所在线基因组数据库）中基因表达的倍数变化与通过特异性小干扰RNA抑制转染人细胞中的SMARCA2以及Smarca2基因敲除小鼠前额叶皮质中的直系同源基因之间存在显著相关性。Smarca2基因敲除小鼠表现出社交互动和前脉冲抑制受损。致幻药物降低了小鼠脑中Smarca2的表达，而抗精神病药物则使其增加。这些发现支持了BRM在精神分裂症病理生理学中发挥作用的观点。
Zotero 插件