The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence

Abstract

Evidence of LRRK2 haplotypes associated with Parkinson's disease (PD) risk was recently found in the Chinese population from Singapore, and a common LRRK2 missense variant, Gly2385Arg, was independently detected as a putative risk factor for PD in the Chinese population from Taiwan. To test the association between the Gly2385Arg variant in a large case-control sample of Chinese ethnicity from Singapore, and to perform functional studies of the wild type and Gly2385Arg LRRK2 protein in human cell lines. In a case-control study involving 989 Chinese subjects, the frequency of the heterozygous Gly2385Arg genotype was higher in PD compared to controls (7.3 vs. 3.6%, odds ratio = 2.1, 95% CI: 1.1-3.9, P = 0.014); these values yield an estimated population attributable risk (PAR) of approximately 4%. In a multivariate logistic regression analysis with the disease group (PD vs. controls) as the dependent variable and the genotype as an independent factor with adjustments made for the effect of age and gender, the heterozygous Gly2385Arg genotype remained associated with an increased risk of PD compared to wild type genotype (odds ratio = 2.67, 95% CI: 1.43-4.99, P = 0.002). The glycine at position 2385 is a candidate site for N-myristoylation, and the Gly2385Arg variant replaces the hydrophobic glycine with the hydrophilic arginine, and increases the net positive charge of the LRRK2 WD40 domain. In transfection studies, we demonstrated that both the wild type and Gly2385Arg variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under condition of oxidative stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis. Our study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the Chinese population. Our bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant is biologically relevant and it might act through pro-apoptotic mechanisms.

Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease

“…Our data support previous studies that mutations of LRRK2 including G2019S mutation is not a common genetic cause in Asian PD [28][29][30]. On the other hand, the G2385R polymorphism of LRRK2 was reported to increase the risk for PD in some Asian PD populations [13][14][15]. Carrier frequencies of G2385R polymorphism of LRRK2 in our data is close to previous reports in Chinese or Japanese which were 5.7-11.6% in PD and 0-4.8% in controls.…”

“…No mutations were found in analyzed exons of UCHL1, DJ-1, and LRRK2. Recently, G2385R polymorphism of LRRK2 was found to increase the risk of PD in Asian population [13][14][15]. In our cohort, 12.5% of Korean EOPD had G2385R polymorphism of LRRK2, whereas 5% of the age-and sex-matched controls had the same variant (p=0.09, OR=2.71, 95%CI=0.87-8.48).…”

The LRRK2 Arg1628Pro variant is a risk factor for Parkinson’s disease in the Chinese population

“…This work led to our initial identification of the association of Gly2385Arg with PD, a finding that has been rapidly and consistently replicated in Chinese populations from Singapore [5], Taiwan [6,7], mainland China [8,9], and in the Japanese population [10].…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Two variants in LRRK2 that are predominantly found in Asian populations, G2385R [93][94][95][96][97] and R1628P [98][99][100][101], increase the lifetime risk of PD about 2-fold [102]. Molecular modeling predicts that the G2385 residue is located on the outer surface of the WD40 domain towards the C-terminus of LRRK2 [31].…”