Manini Arianna, Vasta Rosario, Brusati Alberto, Scheveger Francesco, Peverelli Silvia, Maranzano Alessio, Doretti Alberto, Gentile Francesco, Colombo Eleonora, Brunetti Maura, Moglia Cristina, Canosa Antonio, Manera Umberto, Grassano Maurizio, Gentilini Davide, Messina Stefano, Verde Federico, Morelli Claudia, Landers John E, Traynor Bryan J, Chiò Adriano, Silani Vincenzo, Calvo Andrea, Ratti Antonia, Ticozzi Nicola
Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milan, Italy.
Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
Ann Clin Transl Neurol. 2025 Apr 25;12(7):1499-503. doi: 10.1002/acn3.70059.
This study explored the impact of KIF5A rs113247976 (p.Pro986Leu), a risk allele for amyotrophic lateral sclerosis (ALS), on phenotypic variability in two Italian ALS cohorts (discovery, n = 865; replication, n = 1174). The minor allele (T) frequency was 0.015. No patients were homozygous (TT), allowing comparison between wild type and heterozygous carriers only. Heterozygous carriers showed faster disease progression (ALSFRS-R preslope). Findings were validated across both cohorts. Multiple linear regression identified p.Leu986 and age at onset as ALSFRS-R preslope predictors. In conclusion, heterozygous p.Leu986 in KIF5A is associated with faster ALS progression, supporting its consideration for genetic screening in clinical trials.
本研究探讨了肌萎缩侧索硬化症（ALS）的风险等位基因KIF5A rs113247976（p.Pro986Leu）对两个意大利ALS队列（发现队列，n = 865；复制队列，n = 1174）表型变异性的影响。次要等位基因（T）频率为0.015。没有患者是纯合子（TT），因此仅能在野生型和杂合子携带者之间进行比较。杂合子携带者表现出更快的疾病进展（ALSFRS-R斜率前）。研究结果在两个队列中均得到验证。多元线性回归确定p.Leu986和发病年龄为ALSFRS-R斜率前的预测因子。总之，KIF5A中杂合的p.Leu986与ALS进展更快有关，支持在临床试验中将其纳入基因筛查的考虑范围。
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