Abstract
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3′ splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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Acknowledgments
We thank all the patients for participating in this study. We also thank all the neurologists who provided samples for this study.
Funding
This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas Nos. 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid [H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080] from the Ministry of Health, Welfare and Labour, Japan, and grants (Nos. 15ek0109065h0002, 16kk0205001h001, 17kk0205001h0002, and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to S.T. This work was also supported in part by JSPS KAKENHI (Grant-in-Aid for JSPS Fellows) Grant Number JP19J01720.
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Naruse, H., Ishiura, H., Mitsui, J. et al. Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis. Neurogenetics 22, 11–17 (2021). https://doi.org/10.1007/s10048-020-00626-1
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DOI: https://doi.org/10.1007/s10048-020-00626-1