Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

Claire Guissart,Claire Guissart,Claire Guissart,Claire Guissart,Kevin Mouzat,Anne Polge,Paul Vilquin,Serge Lumbroso,Anne Polge,Serge Lumbroso,Cédric Raoul,Cédric Raoul,Cédric Raoul,Jovana Kantar,Serge Lumbroso,Kevin Mouzat,Jovana Kantar,Serge Lumbroso,Jovana Kantar,Jovana Kantar,Baptiste Louveau,Baptiste Louveau,Paul Vilquin

doi:10.1038/s41598-020-77716-5

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of both upper and lower motoneurons, leading to a progressive paralysis and death within 3–5 years[1]
Regarding the Nonsense-mediated mRNA decay (NMD) rules we estimated that the region of SOD1 obeying the NMD is located between nucleotides 151–301, which correspond to amino acids 50–100 (Fig. 1)
We found a total of 16 disease-associated-Premature termination codons (PTCs) mutations in SOD1 in the literature[15,16], including 4 nonsense mutations, 11 frameshift mutations and 1 deep intronic splicing mutation (Table 1, Fig. 1)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of both upper and lower motoneurons, leading to a progressive paralysis and death within 3–5 years[1]. Over 180 different mutations throughout the five exons of the SOD1 gene (MIM 147450) have been d escribed[2,3], the vast majority of which being missense point mutations resulting in a dominant mode of inheritance of ALS (with the exception of the D91A mutation) and spreading over the entire 154 amino acid s equence[4,5] It has been well-established that SOD1 mutants-mediated toxicity is caused by a gain-of-function rather than the loss of the detoxifying activity of SOD12 and that mutant SOD1 can adopt multiple misfolded conformations that mediate toxicity[2]. Greater than approximately 400 nucleotides inhibit NMD; (4) the start-proximal rule: PTCs located below 150 nucleotides from the start codon typically fail to trigger NMD

Methods

Results

Conclusion