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

Arianna Manini; Rosario Vasta; Alberto Brusati; Francesco Scheveger; Silvia Peverelli; Alessio Maranzano; Alberto Doretti; Francesco Gentile; Eleonora Colombo; Maura Brunetti; Cristina Moglia; Antonio Canosa; Umberto Manera; Maurizio Grassano; Davide Gentilini; Stefano Messina; Federico Verde; Claudia Morelli; John E Landers; Bryan J Traynor; Adriano Chiò; Vincenzo Silani; Andrea Calvo; Antonia Ratti; Nicola Ticozzi

doi:10.1002/acn3.70059

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

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

Authors

Arianna Manini¹, Rosario Vasta^{2

3}, Alberto Brusati⁴, Francesco Scheveger⁵, Silvia Peverelli⁶, Alessio Maranzano⁶, Alberto Doretti¹, Francesco Gentile⁷, Eleonora Colombo⁶, Maura Brunetti², Cristina Moglia^{2

8}, Antonio Canosa^{2

8

9}, Umberto Manera^{2

8}, Maurizio Grassano^{2

8}, Davide Gentilini^{3

10}, Stefano Messina⁶, Federico Verde^{1

6}, Claudia Morelli⁶, 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

¹ Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milan, Italy.
² Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
³ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, Maryland, USA.
⁴ Department of Brain and Behavioral Sciences, Università degli Studi di Pavia, Pavia, Italy.
⁵ Neurology Residency Program, Università degli Studi di Milano, Milan, Italy.
⁶ Department of Neurology-Laboratory of Neuroscience, IRCCS, Istituto Auxologico Italiano, Milan, Italy.
⁷ Biology of Myelin Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁸ Neurology Unit 1U, "City of Health and Science" University Hospital, Turin, Italy.
⁹ Institute of Cognitive Sciences and Technologies, National Council of Research, Rome, Italy.
¹⁰ Bioinformatics and Statistical Genomic Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹¹ Department of Neurology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
¹² Neuroscience Program, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
¹³ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA.
¹⁴ Therapeutics Development Laboratory, National Center for Advancing Translational Sciences, Rockville, Maryland, USA.
¹⁵ Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK.
¹⁶ Department Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.

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.

Abstract

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