Analysis ofSOD1variants in Chinese patients with familial amyotrophic lateral sclerosis

Abstract

Summary Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, and genetic contributors exert a significant role in the complicated pathogenesis. Identification of the genetic causes in ALS families could be valuable for early diagnosis and management. The development of potential drugs for patients with genetic defects will shed new light on ALS therapy. Aim To identify causative variants in three Chinese families with familial ALS (FALS), reveal the pathogenic mechanism, and look for the targeted drug for ALS. Design and methods Whole-exome sequencing and bioinformatics were used to perform genetic analysis of the ALS families. Functional analysis was performed to study the variants’ function and search for potential drug targets. Results Three heterozygous missense variants of the SOD1 gene were identified in families with FALS. The clinical manifestations of these patients include spinal onset, predominant lower motor neurons presentation, and absence of cognitive involvement. Functional analysis showed that all three SOD1 variants led to increased reactive oxygen species (ROS) levels, reduced cell viability, and formation of cytoplasmic aggregates. Remarkably, the decreased cell viability induced by variants was rescued after treatment with the ROS inhibitor N-acetylcysteine. Conclusions This study identified three SOD1 variants in three families with FALS. The variant SOD1 toxicity was associated with oxidative damage and aggregation, and N-acetylcysteine could rescue the decreased cell viability induced by these variants. Our findings support a pathogenic role for ROS in SOD1 deficiencies, and provide a potential drug N-acetylcysteine for ALS therapy, especially in SOD1-patients with limb onset.

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

“…The study further led to the development of a web-utility tool that provides immediate access to and analytical framework of the database [26]. However, a more detailed examination of the study and the web-utility tool revealed a lack of consideration for some regionally prevalent variants in this database, such as R116G (mostly in Germany) [27], L145S (mostly in Poland) [28,29], and C112Y (mostly in Asia) [30][31][32][33][34][35].…”