Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00439-006-0268-0
Title: The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: Genetic and functional evidence
Authors: Tan E.K. 
Zhao Y.
Skipper L.
Tan M.G.
Di Fonzo A.
Sun L.
Fook-Chong S.
Tang S.
Chua E.
Yuen Y.
Tan L.
Pavanni R.
Wong M.C.
Kolatkar P.
Lu C.S.
Bonifati V.
Liu J.J.
Issue Date: 2007
Publisher: Springer
Citation: Tan E.K., Zhao Y., Skipper L., Tan M.G., Di Fonzo A., Sun L., Fook-Chong S., Tang S., Chua E., Yuen Y., Tan L., Pavanni R., Wong M.C., Kolatkar P., Lu C.S., Bonifati V., Liu J.J. (2007). The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: Genetic and functional evidence. Human Genetics 120 (6) : 857-863. ScholarBank@NUS Repository. https://doi.org/10.1007/s00439-006-0268-0
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 ?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. � Springer-Verlag 2006.
Source Title: Human Genetics
URI: http://scholarbank.nus.edu.sg/handle/10635/150185
ISSN: 0340-6717
DOI: 10.1007/s00439-006-0268-0
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