Association of <i>TRMT2B</i> gene variants with juvenile amyotrophic lateral sclerosis

doi:10.1007/s11684-023-1005-y

Front. Med.

2024, Vol. 18

Issue (1) : 68-80 https://doi.org/10.1007/s11684-023-1005-y

Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis

Yanling Liu^1,², Xi He³, Yanchun Yuan⁴, Bin Li^4,^5,⁶, Zhen Liu⁴, Wanzhen Li⁴, Kaixuan Li², Shuo Tan², Quan Zhu², Zhengyan Tang², Feng Han², Ziqiang Wu², Lu Shen^4,^5,^6,^7,^8,⁹, Hong Jiang^4,^5,^6,⁷, Beisha Tang^4,^5,^6,⁷, Jian Qiu^5,^6,^7,¹⁰, Zhengmao Hu⁷(

), Junling Wang^1,^4,^5,^6,^7,^8,⁹(

)

¹. Department of Neurology, Xiangya Hospital, Central South University, Jiangxi, National Regional Center for Neurological Diseases, Nanchang 330038, China
². Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, Department of Urology, Xiangya Hospital, Central South University, Changsha 410078, China
³. Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China
⁴. Department of Neurology, Xiangya Hospital, Central South University, Changsha 410078, China
⁵. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410008, China
⁶. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha 410008, China
⁷. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, China
⁸. Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha 410078, China
⁹. Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha 410078, China
¹⁰. Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha 410078, China

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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

Corresponding Author(s): Zhengmao Hu,Junling Wang

About author:

Li Liu and Yanqing Liu contributed equally to this work.

Just Accepted Date: 31 August 2023 Online First Date: 10 October 2023 Issue Date: 22 April 2024

Cite this article:

Yanling Liu,Xi He,Yanchun Yuan, et al. Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis[J]. Front. Med., 2024, 18(1): 68-80.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1005-y
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I1/68

Fig.1 TRMT2B was identified to be associated with ALS in a JALS family. (A) JALS family recruited from Hunan, China. The black arrow indicated the proband. (B) TRMT2B c.1356G > T; p.K452N variant co-segregated in this family. (C) Highly conserved K452 on TRMT2B protein among species. (D) Patient deformity of hands and feet. (E) Karyotypes of patients and their mother.

Tab.1 Demographic characteristics of patients with ALS

Tab.2 Clinical features of patients with JALS carrying TRMT2B variants

Tab.3 Variations identified within patients with ALS

Fig.2 Altered mitochondrial morphology in patients’ lymphoblastoid cells. (A) TEM images showing reduced numbers of mitochondria in patients. (B) TEM images of lymphoblastoid cells from XY003.P1 (N = 13), XY003.P2 (N = 15), XY003.S1 (N = 7), and unrelated control (N = 10). (C) TEM images showing swollen mitochondria in patients. (D) TEM images of mitochondria from XY003.P1 (N = 120), XY003.P2 (N = 100), XY003.S1 (N = 185), and unrelated control (N = 274). The size of mitochondria in patients increased. **** P < 0.0001.

Fig.3 Altered mitochondrial function in patients’ lymphoblastoid cells. (A) Unchanged TRMT2B expression in patients. (B) Gray density analysis of TRMT2B. (C) Lower protein expression of ND1 in patients. (D) Gray density analysis of ND1 expression. (E) Lower mRNA expression of ND1 in patient-originated lymphoblastoid cells. (F) Decreased complex I activity in patients. (G) Increased ROS levels in patients. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001 by unpaired t-test.

Fig.4 Altered mitochondrial morphology in TRMT2B-interfering HEK293 lines. (A) and (B) Decreased number of mitochondria within TRMT2B-interfering HEK293 cells (N_NC = 13, N_sh = 14). (C,D) Swollen mitochondria within TRMT2B-interfering HEK293 cells (N_NC = 120, N_sh1 = 84, N_sh2 = 79). * P < 0.05, ** P < 0.01, and *** P < 0.001 by unpaired t-test.

Fig.5 Altered mitochondrial function in TRMT2B-interfering HEK293 lines. (A) Decreased ND1 expression by inhibition of TRMT2B expression. (B) Gray density analysis of ND1. (C) Unchanged expression of MTCO1, MTCO2, and TFAM when TRMT2B was interfered. (D) Decreased expression of ND1 in TRMT2B mutated overexpression groups. (E) Gray density analysis of WB lanes of ND1. (F) Increased ROS levels in TRMT2B-interfering HEK293 cells. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001 by unpaired t-test.

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