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Inositol-metabolizing enzyme gene-manipulated mice towards molecular dissection of pathophysiology of mental disorders.

肌醇代谢酶基因操纵小鼠对精神障碍病理生理学进行分子解剖。

基本信息

批准号：
17390323
负责人：
YOSHIKAWA Takeo
金额：
$ 9.98万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390323/
关键词：
lithium Impa1 Impa2 mood stabilizer bipolar disorder gene manipulated mice IMPase inositol 統合失調症熱性けいれんモデルマウス ENU inositol monophosphatase ノックアウトマウス gene-driven mutagenesis トランスジェニックマウス

项目摘要

In this study, we successfully developed mice with manipulated genes for IMPase (inositol monophosphatase) : Impa1-Tg, Impa2-Tg, Impa1-ENU and Impa2-KO mice. Among them, transgenic mice with brain-specific IMPA2 overexpression exhibited moderate anxiety phenotype when evaluated in elevated plus maze (EPM) and light and dark (LD) box tests. Our analysis showed that at least one of three Impa1-ENU lines, where a missense mutation is introduced by a mutagen ENU (ethyl-nitroso-urea) at different position in the coding region of Impal gene, completely losses the enzymatic activity given by the Impal protein.Our study also showed that a promoter haplotype of IMPA2 confers a possible risk for bipolar disorder in Japanese population possibly by enhancing transcription. Taken together with phenotype of Impa2-Tg mice, these data strongly suggest the function of IMPA2 in the pathogenesis of mood disorders, in particular, bipolar disorder.Moreover, we first proved that the IMPA2 protein exhibits IMPase activity in vitro. IMPA1 and IMPA2 show clearly different tissue distributions, and have different sensitivities to lithium. To obtain further insight for the IMPA2 gene product, we first revealed the crystal structure of this protein. While the overall structure of the IMPA2 protein is similar to that of IMPA1, which exhibits lithium-inhibitable strong IMPase activity, IMPA2 possesses more widely opened cavity than that of IMPA1. These observations imply a specific function of IMPA2 in the biochemical process(es) in the cell, possibly having specific in vivo substrate(s), which is different from that for IMPA1.

在这项研究中，我们成功地开发了具有IMPase（肌醇单磷酸酶）操纵基因的小鼠：Impa 1-Tg、Impa 2-Tg、Impa 1-ENU和Impa 2-KO小鼠。其中，脑特异性IMPA 2过表达的转基因小鼠在高架十字迷宫（elevated plus maze，HSK）和明暗箱（light and dark box，LD）测试中表现出中度焦虑表型。我们的分析表明，在3个Impa 1-ENU株系中，至少有一个在Impal基因编码区的不同位置被诱变剂ENU（乙基亚硝基脲）引入错义突变，完全丧失了Impal蛋白所赋予的酶活性，我们的研究还表明，IMPA 2的启动子单倍型可能通过增强转录而赋予日本人群双相情感障碍的风险。结合Impa 2-Tg小鼠的表型，这些数据有力地表明了IMPA 2在心境障碍，特别是双相情感障碍的发病机制中的作用。IMPA 1和IMPA 2显示出明显不同的组织分布，并且对锂具有不同的敏感性。为了进一步了解IMPA 2基因产物，我们首先揭示了这种蛋白质的晶体结构。虽然IMPA 2蛋白的整体结构与IMPA 1的结构相似，但IMPA 1表现出锂可降解的强IMPA酶活性，但IMPA 2具有比IMPA 1更宽的开放腔。这些观察结果暗示了IMPA 2在细胞中的生化过程中的特异性功能，可能具有特异性体内底物，这与IMPA 1不同。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1

DOI：
10.1074/jbc.m604474200
发表时间：
2007-01-05
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Ohnishi, Tetsuo;Ohba, Hisako;Yoshikawa, Takeo
通讯作者：
Yoshikawa, Takeo

Crystal structure of human myo-inositol monophosphatase 2 (IMPA2), the product of the putative susceptibility gene for bipolar disorder, schizophrenia and febrile seizures

人肌醇单磷酸酶 2 (IMPA2) 的晶体结构，该酶是双向情感障碍、精神分裂症和热性惊厥的假定易感基因的产物

DOI：
发表时间：
期刊：
Proteins : Structure, Function, and Bioinformatics (in press)
影响因子：
0
作者：
Ohnishi T et al.;Arai R et al.
通讯作者：
Arai R et al.

A promoter haplotype of inositol monophosphatase 2 gene (IMPA2) at 18p11.2 possibly confers risk for bipolar disorder by enhancing transcription.

18p11.2 肌醇单磷酸酶 2 基因 (IMPA2) 的启动子单倍型可能通过增强转录而增加双相情感障碍的风险。

DOI：
发表时间：
2007
期刊：
Neuropsychopharmacology Jan 24 [Epub ahead of print]
影响因子：
0
作者：
Miyagi S.;Iwane T.;Akamatsu Y.;Nakamura A.;Sato A.;Satomi S.;Ohnishi T et al.;Arai R et al.;Yamada K et al.;Sadakata T et al.;Ohnishi T et al.
通讯作者：
Ohnishi T et al.

Autistic-like phenotypes in CAPS2/CADPS2 knockout mice and aberrant CAPS2 splicing in autistic patients.

CAPS2/CADPS2 敲除小鼠中的自闭症样表型和自闭症患者中的异常 CAPS2 剪接。