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ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk

Authors :
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
Kohichi Tanaka
Source :
Translational Psychiatry, Translational Psychiatry, Vol 10, Iss 1, Pp 1-15 (2020)
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

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.

Details

ISSN :
21583188
Volume :
10
Database :
OpenAIRE
Journal :
Translational Psychiatry
Accession number :
edsair.doi.dedup.....8342a89f4935d91bbf8657d2df1fd11c