Autism Spectrum Disorders (ASD) associated rare loss of function genetic variant in SUV39H2; a putative role of H3K9 methylation dynamics in ASD pathogenesis

2019 年度 実施状況報告書

• 研究課題/領域番号: 19K08084
• 研究機関: 国立研究開発法人理化学研究所
• 研究代表者: SHABEESH BALAN 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (70721588)
• 研究期間 (年度): 2019-04-01 – 2022-03-31
• キーワード: autism / SUV39H2 / H3K9 methyltransferase / variant / behavior

研究実績の概要

We identified the first case of rare SUV39H2 loss of function (LoF) variant in autism spectrum disorders (ASD), indicating the role of impaired H3K9 methylation in genes relevant for ASD pathogenesis. In silico evaluation for structural stability revealed that the LoF variant caused de-stabilizing effect on the protein, when compared to the wild-type. Further, the variant in mouse and human homolog, also showed impaired histone H3 methylation activity in vitro, thus showing SUV39H2 variant can be an upstream event for the genetic perturbations for other ASD relevant genes. To evaluate this, we first generated a Suv39h2-deficient mouse in B6 background, as the variant identified impaired histone H3 methylation. We confirmed reduced H3K9me3 in Suv39h2-deficient mouse brain and are currently evaluating behavioral tests relevant for ASD. We will further perform transcriptomic analysis to identify the genes perturbed by loss of H3K9 methylation which are relevant for ASD.

現在までの達成度 (区分)

1: 当初の計画以上に進展している

理由

We have validated the effect of the SUV39H2 mutation identified in ASD both by in silico and in vitro methods. Taken together we identified that the variant causes impaired histone H3 methylation, which can be an upstream event for the genetic perturbations for other ASD relevant genes. We have successfully generated Suv39h2-deficient mouse which also showed deficits in H3K9me3 activity in brain.

今後の研究の推進方策

We are currently evaluating the behaviors relevant for ASD and molecular perturbation resulting from impaired H3K9me3 in Suv39h2-deficient mouse.

次年度使用額が生じた理由

Some of the mice were not procured in time, but there was no problem to carry out the research, which will be procured in the next year.

研究成果

• [雑誌論文] Evidence for Altered Metabolism of Sphingosine-1-phosphate in the Corpus Callosum of Patients with Schizophrenia (2020)
  • 著者名/発表者名: Esaki, K., Balan, S., Iwayama, Y., Shimamoto-Mitsuyama, C., Hirabayashi, Y., Dean, B. & Yoshikawa, T.
  • 雑誌名: Schizophrenia Bulletin 巻: - ページ: -
  • DOI: 10.1093/schbul/sbaa052
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology (2019)
  • 著者名/発表者名: Ide, M., Ohnishi, T#, Toyoshima, M., Balan, S., Maekawa, M., Shimamoto-Mitsuyama, C., Iwayama, Y., Ohba, H., Watanabe, A., …, &., Yoshikawa, T.
  • 雑誌名: EMBO Molecular Medicine 巻: e10695 ページ: -
  • DOI: 10.15252/emmm.201910695
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Enhanced Carbonyl Stress Induces Irreversible Multimerization of CRMP2 in Schizophrenia Pathogenesis. (2019)
  • 著者名/発表者名: Toyoshima, M., Jiang, X. , Ogawa, T. , Ohnishi, T. , Yoshihara, S. , Balan, S. , Yoshikawa, T., & Hirokawa, N
  • 雑誌名: Life Science Alliance 巻: 2:e201900478 ページ: -
  • DOI: 10.26508/lsa.201900478
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Investigation of betaine as a novel psychotherapeutic for schizophrenia (2019)
  • 著者名/発表者名: Ohnishi, T. #, Balan, S. #, Toyoshima, M., Maekawa, M., Ohba, H., Watanabe, A., Iwayama, Y., Fujita, Y., Tan, Y., Hisano, Y., Shimamoto-Mitsuyama, C., Nozaki, Y., Esaki, K., Nagaoka, A., Matsumoto, J., Hino, M., Mataga, N., Hayashi-Takagi, A., Hashimoto, K., Kunii, Y., Kakita, A., Yabe, H., 2 & Yoshikawa, T
  • 雑誌名: EbioMedicine 巻: 45 ページ: 432-446
  • DOI: DOI: 10.1016/j.ebiom.2019.05.062
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice. (2019)
  • 著者名/発表者名: Shimamoto-Mitsuyama, C., Ohnishi, T., Balan, S., Ohba, H., Watanabe, A., Maekawa, M., Hisano, Y., Iwayama, Y., Owada, Y., & Yoshikawa, T.
  • 雑誌名: Schizophrenia Research 巻: - ページ: -
  • DOI: DOI: 10.1016/j.schres.2019.02.002
  • 査読あり / 国際共著
• [学会発表] Genetic determinants of epigenetic modifications contributing to the ASD pathogenesis’ (2019)
  • 著者名/発表者名: Shabeesh Balan
  • 学会等名: Symposium on Autism at the 6th Congress of Asian College of Neuropsychopharmacology (AsCNP)
  • 国際学会 / 招待講演