モデルマウスを用いた、正常眼圧緑内障家系で同定された新規原因遺伝子Xの機能解析

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K18366
• Research Institution: 独立行政法人国立病院機構(東京医療センター臨床研究センター)
• Principal Investigator: 潘 洋 独立行政法人国立病院機構(東京医療センター臨床研究センター), 分子細胞生物学研究部, 研究員 (20866389)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: Genetic diseases / Mouse models / Ophthalmology / iPS cells

Outline of Annual Research Achievements

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by RGC death leading to cupping of the optic nerve head and visual field loss at normal IOP. The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the METTL23 gene. This mutation caused mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-KI mice developed a NTG phenotype. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23-KI mice. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina which was required for the NF-κB-mediated TNF-α and IL-1β feedback.

Research Products

• [Journal Article] METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma (2022)
  • Author(s): Pan Yang、Suga Akiko、Kimura Itaru、Kimura Chojiro、Minegishi Yuriko、Nakayama Mao、Yoshitake Kazutoshi、Iejima Daisuke、Minematsu Naoko、Yamamoto Megumi、Mabuchi Fumihiko、Takamoto Mitsuko、Shiga Yukihiro、Araie Makoto、Kashiwagi Kenji、Aihara Makoto、Nakazawa Toru、Iwata Takeshi
  • Journal Title: Journal of Clinical Investigation Volume: 132 Pages: e153589
  • DOI: 10.1172/JCI153589
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration (2022)
  • Author(s): Pan Yang、Fu Yingbin、Baird Paul N.、Guymer Robyn H.、Das Taraprasad、Iwata Takeshi
  • Journal Title: Progress in Retinal and Eye Research Volume: online ahead of print Pages: 101159～101159
  • DOI: 10.1016/j.preteyeres.2022.101159
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HTRA1 Regulates Subclinical Inflammation and Activates Proangiogenic Response in the Retina and Choroid (2022)
  • Author(s): Ahamed Waseem、Yu Richard Ming Chuan、Pan Yang、Iwata Takeshi、Barathi Veluchamy Amutha、Wey Yeo Sia、Tun Sai Bo Bo、Qiu Beiying、Tan Alison、Wang Xiaomeng、Cheung Chui Ming Gemmy、Wong Tien Yin、Yanagi Yasuo
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Pages: 10206～10206
  • DOI: 10.3390/ijms231810206
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Dominant Mutation in METTL23 gene is responsible for Normal tension glaucoma (2022)
  • Author(s): Pan Yang
  • Organizer: The XXVth Biennial Meeting of the International Society of Eye Research (ISER) 2023
  • Int'l Joint Research
• [Presentation] METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma (2022)
  • Author(s): Pan Yang
  • Organizer: 第15回RRM
• [Presentation] Dominant Mutation in X gene is responsible for Normal Tension Glaucoma (2022)
  • Author(s): Pan Yang
  • Organizer: 第1回NHOネットワーク共同研究 感覚器グループ会議・班会議
• [Remarks] 正常眼圧緑内障の新たな原因発症メカニズムの解明 ― エピジェネティックスと緑内障 ―
  • URL: https://www.tohoku.ac.jp/japanese/2022/10/press20221031-01-glaucoma.html