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Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan

Journal of Human Genetics volume 65, pages 771–781 (2020)Cite this article

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Abstract

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson’s disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers, 16K09678 (to KN), 16K09700 (to YL), 16K09676 (to MF), 15H04842 (to NH), and the Canada Research Chairs program (AJS). We are very grateful for these grants: AMED-CREST (Japanese Association of Medical Research and Development) (NH), Practical Research Project for Rare/Intractable Diseases from AMED; 15ek0109029s0202 to NH. This work was carried out (in part) at the Intractable Disease Research Center, Juntendo University Graduate School of Medicine. The study was partly supported by a research grant from Biogen Japan Ltd (KN).

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Authors and Affiliations

  1. Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Yuanzhe Li, Aya Ikeda, Genko Oyama, Kensuke Daida, Arisa Hayashida, Kotaro Ogaki, Masashi Takanashi, Manabu Funayama, Kenya Nishioka & Nobutaka Hattori

  2. Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Hiroyo Yoshino, Manabu Funayama & Nobutaka Hattori

  3. Department of Neurology, Masuda Red Cross Hospital, I 103-1 Otoyoshi-cho, Masuda-shi, Shimane, 698-8501, Japan

    Mitsuhiro Kitani

  4. Department of Neurology, Asahikawa Medical Center, National Hospital Organization, 4048 Hanasaki-cho 7-chome, Asahikawa, Hokkaido, Japan

    Kousuke Yoshida & Takashi Kimura

  5. Department of Neurology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8510, Japan

    Yoshiaki Nakayama & Hidefumi Ito

  6. Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Naoto Sugeno & Masashi Aoki

  7. Department of Neurology, Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan

    Hiroaki Miyajima

  8. Department of Neurology, Yokohama City University Medical Center, 4-57 Urafunecho, Minami-ku, Yokohama, 232-0024, Japan

    Katsuo Kimura & Naohisa Ueda

  9. Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan

    Masao Watanabe & Takao Urabe

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  1. Yuanzhe Li
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Li, Y., Ikeda, A., Yoshino, H. et al. Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan. J Hum Genet 65, 771–781 (2020). https://doi.org/10.1038/s10038-020-0772-4

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