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. 2025 Apr 25;12(7):1499-1503.
doi: 10.1002/acn3.70059. Online ahead of print.

KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis

Arianna Manini  1 , Rosario Vasta  2   3 , Alberto Brusati  4 , Francesco Scheveger  5 , Silvia Peverelli  6 , Alessio Maranzano  6 , Alberto Doretti  1 , Francesco Gentile  7 , Eleonora Colombo  6 , Maura Brunetti  2 , Cristina Moglia  2   8 , Antonio Canosa  2   8   9 , Umberto Manera  2   8 , Maurizio Grassano  2   8 , Davide Gentilini  3   10 , Stefano Messina  6 , Federico Verde  1   6 , Claudia Morelli  6 , John E Landers  11   12 , Bryan J Traynor  3   13   14   15 , Adriano Chiò  2   8   9 , Vincenzo Silani  1   6 , Andrea Calvo  2   9 , Antonia Ratti  6   16 , Nicola Ticozzi  1   6
Affiliations

KIF5A p.Pro986Leu Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis

Arianna Manini et al. Ann Clin Transl Neurol. .

Abstract

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.

Keywords: KIF5A; alleles; amyotrophic lateral sclerosis; disease progression; motor neurons.

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Conflict of interest statement

V.S. received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb Srl, Novartis Pharma AG, and Zambon Biotech SA. He is on the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. N.T. received compensation for consulting services from Amylyx Pharmaceuticals, Biogen, Italfarmaco, and Zambon Biotech SA. He is Associate Editor for Frontiers in Aging Neuroscience.

Figures

FIGURE 1
FIGURE 1
(A–C) Distribution of the ALSFRS‐R preslope according to the KIF5A rs113247976 genotypes (p.Pro986 and p.986Leu). (A) Discovery cohort (n = 449). (B) Replication cohort (n = 1174). (C) Aggregate analysis of discovery and replication cohorts (n = 1623). The non‐parametric Wilcoxon‐Mann–Whitney was run for the analysis. In the boxplots, the bold line shows the median, the gray box includes the middle 50% of the data and whiskers indicate the minimum and maximum values. Empty circles represent outliers. (D) Plot reflecting the multiple linear regression model predicting the preslope of the ALSFRS‐R using the rs113247976 KIF5A genotype and age at onset. The x‐axis represents age at onset; the y‐axis indicates the preslope of the ALSFRS‐R. The two lines (red and light blue) represent the regression relationship for the two different genotypes of the KIF5A rs113247976 (i.e., p.986Leu vs. p.Pro986). Data points show observed values of ALSFRS‐R preslope for corresponding ages at onset, differentiated by KIF5A rs113247976 genotype status.
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