Association of TRMT2B Gene Variants with Juvenile Amyotrophic Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is characterized by progressive degeneration of motor neurons and demonstrates high clinical heterogeneity and complex genetic architecture. We identified a variation within TRMT2B (c.1356G > T; p.K452N) to be associated with ALS in a family comprising two patients with juvenile ALS. Then, two missense variations and one splicing variation were identified in 10 ALS patients in our cohort with 910 ALS patients, and three more variations were identified in a publicly ALS database (ALSdb) including 2800 ALS patients. Functionally, we detected a decrease of mitochondrial complex I activities in patients originated Epstein-Barr virus–transformed lymphoblastoid cell lines due to decreased number of mitochondria and lower expression of ND1 in mitochondria. Further, we detected increasing ROS but decreased p62 expression alteration within patients. In conclusion, we identified a novel ALS-associated gene, TRMT2B , and broaden the clinical and genetic spectrum of ALS.