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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    ABSTRACT: The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson's disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P = 0.019) and 1.2-fold (P = 0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.
    BioMed Research International 08/2014; 2014:867321. DOI:10.1155/2014/867321 · 2.71 Impact Factor
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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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    ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disease resulting from complex interaction involving genetic and environmental risk factors on background of aging. In terms of genetic risk factors, recent studies provided a growing number of evidence for the idea that certain polymorphisms in familiar Parkinsonism genes may contribute to risk for sporadic PD in populations of specific ethnic backgrounds. To address this issue, a case-control study was conducted to determine the prevalence of LRRK2 Pro755Leu variant in 401 patients with sporadic PD and 398 unrelated healthy controls in Han population from mainland China. Heterozygous LRRK2 Pro755Leu variant was found in four patients and two healthy controls, but no statistical differences in genotypic or allelic frequencies between PD and control groups (genotype: P=0.686; allele: P=0.687) were detected. Furthermore, to evaluate its role in ethnic Chinese population, a meta-analysis was performed on Pro755Leu in population of Chinese ancestry throughout Asia. And it was detected at a similar frequency in PD and control cohort (Z=0.48, P=0.63, odds ratio=1.44, 95% CI: 0.32-6.40). Given these findings, it was quite reasonable to suppose that LRRK2 Pro755Leu variant rarely increased risk for PD in ethnic Chinese population in Asia.
    Neuroscience Letters 03/2011; 495(1):35-8. DOI:10.1016/j.neulet.2011.03.030 · 2.06 Impact Factor
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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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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are known to cause typical, late-onset familial Parkinson's disease in different geographic origins. However, there was no report about mutations of LRRK2 gene in mainland China. The 51 coding exons and intron/exon boundaries of the LRRK2 gene were sequenced in nine families with Parkinson's disease. A novel LRRK2 missense mutation resulting in a single amino acid substitution K616R was present in one family with a dominant form of PD, and not in 200 controls. The patient presented with slowly progressive resting tremor, dyskinesia, and responded well to l-dopa. In conclusion, we identified a novel mutation in LRRK2 gene, which was the first mutation of LRRK2 found in the mainland Chinese population with familial Parkinson's disease.
    Neuroscience Letters 10/2009; 468(3):198-201. DOI:10.1016/j.neulet.2009.10.080 · 2.06 Impact Factor
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