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.
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References
Abou-Sleiman PM, Muqit MM, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat Rev Neurosci 7(3):207–219
Biskup S, Mueller JC, Sharma M et al (2005) Common variants of LRRK2 are not associated with sporadic Parkinson’s disease. Ann Neurol 58:905–908
Di Fonzo A, Rohe CF, Ferreira J et al (2005) A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson’s disease. Lancet 365:412–415
Di Fonzo A, Wu-Chou YH, Lu CS et al (2006a) A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics (Epub ahead of print)
Di Fonzo A, Tassorelli C, De Mari M et al (2006b) Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson’s disease. Eur J Hum Genet 14:322–331
Fung HC, Chen CM, Hardy J, Hernandez D, Singleton A, Wu YR (2006) Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson’s disease. Mov Disord (Epub ahead of print)
Gilks WP, Abou-Sleiman PM, Gandhi S et al (2005) A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 365:415–416
Gloeckner CJ, Kinkl N, Schumacher A et al (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15:223–232
Goldwurm S, Di Fonzo A, Simons EJ et al (2005) The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor. J Med Genet 42:e65
Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184
Hulo N, Bairoch A, Bulliard V et al (2006) The PROSITE database. Nucleic Acids Res 34(Database issue):D227–D230
Kachergus J, Mata IF, Hulihan M et al (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant Parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 76:672–680
Lesage S, Leutenegger A-L, Ibanez P et al (2005) LRRK2 haplotype analyses in European and North African families with Parkinson’s disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 77:330–332
Lesage S, Durr A, Tazir M et al (2006) LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabs. N Engl J Med 354:422–423
Lu CS, Simons EJ, Wu-Chou YH et al (2005) The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson’s disease. Parkinsonism Relat Disord 11:521–522
Mata IF, Kachergus JM, Taylor JP et al (2005) LRRK2 pathogenic substitutions in Parkinson’s disease. Neurogenetics 6:171–177
Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (2006) LRRK2 in Parkinson’s disease: protein domains and functional insights. Trends Neurosci 29(5):286–293
Ozelius LJ, Senthil G, Saunders-Pullman R et al (2006) LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 354:424–425
Paisan-Ruiz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600
Paisan-Ruiz C, Lang AE, Kawarai T et al (2005) LRRK2 gene in Parkinson disease: mutation analysis and case control association study. Neurology 65:696–700
Paisan-Ruiz C, Evans EW, Jain S et al (2006) Testing association between LRRK2 and Parkinson’s disease and investigating linkage disequilibrium. J Med Genet 43(2):e9
Sakurai N, Utsumi T (2006) Posttranslational N-myristoylation is required for the anti-apoptotic activity of human tGelsolin, the C-terminal caspase cleavage product of human gelsolin. J Biol Chem 281(20):14288–14295
Skipper L, Shen H, Chua E et al (2005a) Analysis of LRRK2 functional domains in nondominant Parkinson disease. Neurology 65(8):1319–1321
Skipper L, Li Y, Bonnard C et al (2005b) Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson’s disease. Hum Mol Genet 14:3549–3556
Tan EK, Shen H, Tan LC et al (2005a) The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson’s disease patients. Neurosci Lett 384:327–329
Tan EK, Puong KY, Chan DK et al (2005b) Impaired transcriptional upregulation of Parkin promoter variant under oxidative stress and proteasomal inhibition: clinical association. Hum Genet 118(3–4):484–488
Tan EK, Skipper L, Chua E et al (2006) Analysis of 14 LRRK2 mutations in Parkinson’s plus syndromes and late-onset Parkinson’s disease. Mov Disord (Epub ahead of print)
Vilas GL, Corvi MM, Plummer GJ, Seime AM, Lambkin GR, Berthiaume LG (2006) Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. Proc Natl Acad Sci USA 103(17):6542–6547
West AB, Moore DJ, Biskup S et al (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842–16847
Zha J, Weiler S, Oh KJ et al (2000) Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290:1761–1765
Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44:601–607
Acknowledgments
The study was supported by the National Medical Research Council, Genome Institute of Singapore, Biomedical Research Council, Department of Clinical Research, Singapore General Hospital. We thank Drs Liu Ed, Lee WL and Aw SE for their support.
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Tan, E.K., Zhao, Y., Skipper, L. et al. The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence. Hum Genet 120, 857–863 (2007). https://doi.org/10.1007/s00439-006-0268-0
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DOI: https://doi.org/10.1007/s00439-006-0268-0