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

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.
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https://www.hal.inserm.fr/inserm-03171291
Contributor : Cédric Raoul <>
Submitted on : Tuesday, March 16, 2021 - 8:02:20 PM
Last modification on : Thursday, April 15, 2021 - 3:08:17 PM

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Claire Guissart, Kevin Mouzat, Jovana Kantar, Baptiste Louveau, Paul Vilquin, et al.. Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.20738. ⟨10.1038/s41598-020-77716-5⟩. ⟨inserm-03171291⟩

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