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The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: Genetic and functional evidence

Erasmus MC, Rotterdam, South Holland, Netherlands
Human Genetics (Impact Factor: 4.52). 03/2007; 120(6):857-63. DOI: 10.1007/s00439-006-0268-0
Source: PubMed

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.

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    • "Taiwan 305 PD, 176 controls OR 17.00 (í µí±ƒ = 0.0002) Farrer et al., 2007 [21] Taiwan 410 PD, 335 controls OR 2.24 (í µí±ƒ = 0.014) Tan et al., 2007 [14] Singapore 495 PD, 494 controls OR 2.14 (í µí±ƒ = 0.014) Tan et al., 2007 [16] Non-Chinese "
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    • "Moreover, some variants in LRRK2 appeared to be susceptive for elevating risk for PD. Gly2385Arg, initially identified in one family from Taiwan [18], was significantly more frequent in sporadic PD patients than in controls in Taiwan, Singapore and some regions in mainland China [1] [3] [7] [8] [11] [31]. It was therefore considered to be the firstly identified LRRK2 variant accounting for increased risk for PD in ethnic Chinese, and also in Japanese and Korean population throughout the Asia [9] [14] [37]. "
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    • "This patient presented with late-onset symptoms of resting tremor, dyskinesia, progressing slowly, and had a good response to l-dopa, which is similar to that described for LRRK2-linked cases. We also identified a G2385R variant and the R1628P variant, which have been reported as risk factors for PD in Asia [20] [21] [22] [23] [24] [25]. In contrast to previous reports, the most common mutation (G2019S; 6055G>A) so far was not detected in any of the families investigated. "
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