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.

肌萎缩侧索硬化症（ALS）是最常见和最严重的成人运动神经元疾病，目前尚无有效的治疗方法。大约 20% 的家族性 ALS 病例是由编码铜/锌超氧化物歧化酶 ( SOD1 ) 的基因显性遗传突变引起的，SOD1 是 ALS 最常见的遗传原因之一。尽管绝大多数导致 ALS 的SOD1错义突变，但少数过早终止密码子 (PTC) 已被识别。众所周知，含有 PTC 的 mRNA 会被无义介导的 mRNA 衰减 (NMD) 迅速降解，从而限制了截短蛋白质的产生。 NMD 监测规则随 PTC 在 mRNA 中的位置而变化，我们分析了 PTC 在SOD1 mRNA 中的定位，以评估这些 PTC 是否可以被 NMD 途径触发降解。我们的研究表明，迄今为止SOD1中描述的所有致病性 PTC 理论上都可以逃脱 NMD，从而产生截短的蛋白质。这一发现支持这样的假设，即单倍体不足不是SOD1突变相关 ALS 的潜在机制，并表明在触发 NMD 的区域中发现的 PTC 不具有致病性。鉴于SOD1反义策略的可用性，考虑到变异治疗分配，这种考虑尤为重要。