<i>KIF5A</i><scp>p.Pro986Leu</scp> Risk Variant and Accelerated Progression of Amyotrophic Lateral Sclerosis
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.
Authors
- Silvia Peverelli (ORCID: https://orcid.org/0000-0002-3226-1112)
- Antonio Canosa (ORCID: https://orcid.org/0000-0001-5876-4079)
- John E. Landers (ORCID: https://orcid.org/0000-0001-8084-5043)
- Francesco Scheveger
- Antonia Ratti (ORCID: https://orcid.org/0000-0002-4264-6614)
- Vincenzo Silani (ORCID: https://orcid.org/0000-0002-7698-3854)
- Bryan J. Traynor (ORCID: https://orcid.org/0000-0003-0527-2446)
- Claudia Morelli (ORCID: https://orcid.org/0000-0003-4027-958X)
- Nicola Ticozzi (ORCID: https://orcid.org/0000-0001-5963-7426)
- Francesco Gentile (ORCID: https://orcid.org/0000-0002-1847-5608)
- Andrea Calvo (ORCID: https://orcid.org/0000-0002-5122-7243)
- Umberto Manera (ORCID: https://orcid.org/0000-0002-9995-8133)
- Alessio Maranzano (ORCID: https://orcid.org/0000-0002-3642-9584)
- Davide Gentilini (ORCID: https://orcid.org/0000-0002-8391-0725)
- Federico Verde (ORCID: https://orcid.org/0000-0002-3977-6995)
- Rosario Vasta (ORCID: https://orcid.org/0000-0002-0393-4736)
- Alberto Brusati (ORCID: https://orcid.org/0000-0003-0686-8030)
- Arianna Manini (ORCID: https://orcid.org/0000-0003-3352-5228)
- Alberto Doretti (ORCID: https://orcid.org/0000-0002-1015-7365)
- Cristina Moglia (ORCID: https://orcid.org/0000-0001-7377-7222)
- Eleonora Colombo (ORCID: https://orcid.org/0000-0001-9062-4850)
- Adriano Chiò (ORCID: https://orcid.org/0000-0001-9579-5341)
- Stefano Messina
- Maura Brunetti
- Maurizio Grassano
Institutions
- Johns Hopkins University (US)
- Vita-Salute San Raffaele University (IT)
- University of Massachusetts Chan Medical School (US)
- University of Milan (IT)
- University of Pavia (IT)
- University Medical Center (US)
- IRCCS Istituto Auxologico Italiano (IT)
- National Institute on Aging (US)
- National Center for Advancing Translational Sciences (US)
- Piedmont Reference Center for Epidemiology and Cancer Prevention (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Ferrari (Italy) (IT)
- Institute of Cognitive Sciences and Technologies (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University College London (GB)
- University of Turin (IT)
Publication Details
- Journal
- Annals of Clinical and Translational Neurology
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1002/acn3.70059
- Citations
- 2
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- Università degli Studi di Milano
- Dipartimenti di Eccellenza
- Ministero della Salute
- National Institutes of Health
- Center for Neurotechnology, University of Washington
- National Institute on Aging