Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan
Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan
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DOI：
10.1038/s10038-020-0772-4
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发表时间：
2020-05-13
影响因子：
3.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Li, Yuanzhe;Ikeda, Aya;Hattori, Nobutaka
富含亮氨酸重复序列激酶2（LRRK2）的变异体是家族性帕金森病（PD）最常见的遗传原因。我们的目的是通过筛查三个外显子（31、41和48）中的LRRK2变体，研究日本PD和LRRK2变体患者的遗传和临床特征，其中包括以下致病性突变：p.R1441C、p.R1441G、p.R1441H、p.G2019S和p.I2020T。在此，我们获得了来自1402例PD患者（653例散发性PD和749例家族性PD）的包含LRRK2变体的数据。结果，我们成功地检测到致病性变体（4个具有p.R1441G，5个具有p.R1441H，7个具有p.G2019S，7个具有p.I2020T）和其他罕见变体（2个具有p.V1447M，1个具有p.V1450I，1个具有p.T1491delT，1个具有p.H2391Q）。在10例和146例患者中分别发现了两种风险变异p.P1446L和p.G2385R。大多数患者表现出类似于常见PD类型的症状，如中年发病、震颤、运动不能、僵硬和步态障碍。很少观察到自主神经功能障碍、认知下降和精神病。通过单倍型分析证明，在我们的队列中，每种已知的致病性变体都有不同的创始人。世代研究表明，LRRK2变体p.G2019S和p.I2020T分别在3500年和1300年前衍生。我们的研究结果概述了日本队列中LRRK2变异的患病率和分布。
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.