1. ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk
- Author
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Akiko Kodama, Kozo Kaibuchi, Takashi Okada, Tomomi Aida, Branko Aleksic, Makoto Arai, Maeri Yamamoto, Teppei Shimamura, Mutsuki Amano, Hidekazu Kato, Toshitaka Nabeshima, Masahito Sawahata, Emiko Shishido, Akira Sobue, Kazuhiro Hada, Taku Nagai, Chikara Mizukoshi, Nakao Iwata, Mariko Sekiguchi, Mio Shinno, Itaru Kushima, Norio Ozaki, Ryosuke Ikeda, Ryota Hashimoto, Akira Yoshimi, Toshiya Inada, Norimichi Ito, Hisako Kubo, Masahiro Nakatochi, Kiyofumi Yamada, Tetsuya Takano, Keisuke Kuroda, Tetsushi Sakuma, Jingrui Xing, Keita Tsujimura, Kanako Ishizuka, Yuto Takasaki, Yuko Arioka, Daisuke Mori, Hiroki Kimura, Masashi Ikeda, Takashi Yamomoto, Chenyao Wang, Yanjie Yu, and Kohichi Tanaka
- Subjects
0301 basic medicine ,RHOA ,DNA Copy Number Variations ,Neurite ,RhoGAP domain ,Molecular neuroscience ,Biology ,Article ,lcsh:RC321-571 ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Animals ,Humans ,Small GTPase ,Clinical genetics ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,GTPase-Activating Proteins ,Phenotype ,Cell biology ,Psychiatry and Mental health ,030104 developmental biology ,Schizophrenia ,biology.protein ,Signal transduction ,rhoA GTP-Binding Protein ,Neural development ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.
- Published
- 2020