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

Mariko Sekiguchi, Akira Sobue, Itaru Kushima, Chenyao Wang, Yuko Arioka, Hidekazu Kato, Akiko Kodama, Hisako Kubo, Norimichi Ito, Masahito Sawahata, Kazuhiro Hada, Ryosuke Ikeda, Mio Shinno, Chikara Mizukoshi, Keita Tsujimura, Akira Yoshimi, Kanako Ishizuka, Yuto Takasaki, Hiroki Kimura, Jingrui XingYanjie Yu, Maeri Yamamoto, Takashi Okada, Emiko Shishido, Toshiya Inada, Masahiro Nakatochi, Tetsuya Takano, Keisuke Kuroda, Mutsuki Amano, Branko Aleksic, Takashi Yamomoto, Tetsushi Sakuma, Tomomi Aida, Kohichi Tanaka, Ryota Hashimoto, Makoto Arai, Masashi Ikeda, Nakao Iwata, Teppei Shimamura, Taku Nagai, Toshitaka Nabeshima, Kozo Kaibuchi, Kiyofumi Yamada, Daisuke Mori, Norio Ozaki

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Article number247
JournalTranslational psychiatry
Volume10
Issue number1
DOIs
Publication statusPublished - 01-12-2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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