Pathogenicity classification of SOD1 variants of uncertain significance by in vitro aggregation propensity

• Published in: Neurobiology of aging 2023-03, Vol.123, p.182-190
• Main Authors: Chen, Lu-Xi, Xu, Hai-Feng, Lin, Hui-Xia, Yang, Xin-Xia, Li, Hong-Fu, Wu, Zhi-Ying
• Format: Article
• Language: English
• Subjects: Aggregation propensity; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; Humans; Mutation; Pathogenicity; Protein Folding; SOD1; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Virulence
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2022.10.008

•We reclassify the pathogenicity of all the SOD1 variants of uncertain significance.•91.2% (31/34) SOD1 VUS variants were confirmed as likely pathogenic.•Aggregation propensity assay is reliable for pathogenicity classification.•Missense SOD1 mutations were mainly located in the C-terminal of SOD1 gene. Deposition of insoluble SOD1 aggregates in motor neurons is the hallmark of SOD1-associated ALS. Mutant SOD1 protein promotes structural instability that leads to misfolded SOD1 protein aggregates, which can be recapitulated in vitro. Therefore, aggregation propensity in cell lines can be a reliable indicator for the pathogenicity classification of SOD1 variants. Herein, we performed in vitro experiment to classify the pathogenicity of 34 SOD1 variants of uncertain significance (VUS) from 215 variants reported previously. The clinical features of 234 ALS patients with 31 SOD1 likely pathogenic (LP) variants were summarized. 31 VUS variants formed aggregates spontaneously, indicating LP variants. Missense variants were mainly located in the C-terminal of SOD1. Among patients with 31 SOD1 LP variants, 75% of patients had lower limb onset. The onset of familial ALS patients (45.7±14.0 years) is earlier than sporadic ALS patients (50.6±13.1 years). Our results expand the spectrum of SOD1 mutations and highlight the natural history of SOD1-positive ALS patients for further clinical trials in SOD1-related ALS.