Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.

Keywords

TRMT2B / amyotrophic lateral sclerosis / mitochondrial complex I / tRNA methylation / reactive oxygen species

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Acknowledgements

The authors wish to thank the patients and their families for their participation in this project. This work was supported by the Program of the National Natural Science Foundation of China (Nos. 82171431 and 31972886), the Natural Science Fund for Distinguished Young Scholars of Hunan Province, China (Nos. 2020JJ2057 and 2021JJ10074), Natural Science Foundation of Changsha City (No. kq2208402), the Program of the National Natural Science Foundation of Hunan Province (No. 2021JJ40989), the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital (No. 2020LNJJ13), the Science and Technology Innovation 2030 (STI2030-Major Projects, No. 2021ZD0201803), the National Key R&D Program of China (No. 2021YFA0805202) the Innovation Team Project of Hunan Province (No. 2019RS1010), and the Innovation Team Project of Central South University (No. 2020CX016).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1005-y and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Yanling Liu, Xi He, Yanchun Yuan, Bin Li, Zhen Liu, Wanzhen Li, Kaixuan Li, Shuo Tan, Quan Zhu, Zhengyan Tang, Feng Han, Ziqiang Wu, Lu Shen, Hong Jiang, Beisha Tang, Jian Qiu, Zhengmao Hu, and Junling Wang declare that they have no conflict of interest.

This study was approved by the Ethics Committee of Xiangya Hospital, Central South University, China. The approved number is 202103191. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. All participants provided written informed consent to the study. The authors affirm that human research participants provided informed consent for the publication of the images in Fig.1 and Fig. S1.

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