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month download article/chapter lrrk2 wd40 domain large case-control sample abou-sleiman pm common genetic variation increased kinase activity full article pdf gly2385arg lrrk2 protein investigating linkage disequilibrium privacy choices/manage cookies study lends support lrrk2 mutation linked anti-apoptotic activity common lrrk2 mutation biomedical research council heterozygous gly2385arg genotype chang gung university putative risk factor g2019s lrrk2 mutation common missense variant lrrk2 gly2385arg variant parkin promoter variant human cell lines common risk factor lrrk2 haplotype analyses lrrk2 pathogenic substitutions check access instant access g2019s mutation dating pro-apoptotic mechanisms chinese population lrrk2 reveals evidence gly2385arg variant replaces scope submit manuscript net positive charge database issue autosomal dominant parkinsonism north african arabs impaired transcriptional upregulation autosomal-dominant parkinsonism drs liu ed lrrk2 functional domains conditions privacy policy wild type genotype related subjects wu-chou yh north african families protein domains article tan late onset parkinson

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         headline:The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence
         description: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.
         datePublished:2006-09-30T00:00:00Z
         dateModified:2006-09-30T00:00:00Z
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         pageEnd:863
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            WD40 Domain
            LRRK2 Mutation
            LRRK2 Gene
            LRRK2 Protein
            Human Genetics
            Molecular Medicine
            Gene Function
            Metabolic Diseases
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      headline:The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence
      description: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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      dateModified:2006-09-30T00:00:00Z
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      pageEnd:863
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         Population Attributable Risk
         WD40 Domain
         LRRK2 Mutation
         LRRK2 Gene
         LRRK2 Protein
         Human Genetics
         Molecular Medicine
         Gene Function
         Metabolic Diseases
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               type:PostalAddress
            type:Organization
      name:Y. Yuen
      affiliation:
            name:Singapore General Hospital
            address:
               name:Department of Health Screening, Singapore General Hospital, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:L. Tan
      affiliation:
            name:National Neuroscience Institute
            address:
               name:National Neuroscience Institute, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:R. Pavanni
      affiliation:
            name:Singapore General Hospital
            address:
               name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
               type:PostalAddress
            type:Organization
            name:SingHealth Research
            address:
               name:SingHealth Research, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:M. C. Wong
      affiliation:
            name:Singapore General Hospital
            address:
               name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
               type:PostalAddress
            type:Organization
            name:SingHealth Research
            address:
               name:SingHealth Research, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:P. Kolatkar
      affiliation:
            name:Genome Institute of Singapore
            address:
               name:Population Genetics, Genome Institute of Singapore, Singapore, Singapore
               type:PostalAddress
            type:Organization
      name:C. S. Lu
      affiliation:
            name:Chang Gung University
            address:
               name:Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-yuan, Taiwan
               type:PostalAddress
            type:Organization
      name:V. Bonifati
      affiliation:
            name:Erasmus MC Rotterdam
            address:
               name:Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:J. J. Liu
      affiliation:
            name:Genome Institute of Singapore
            address:
               name:Population Genetics, Genome Institute of Singapore, Singapore, Singapore
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
      name:National Neuroscience Institute, Singapore, Singapore
      name:SingHealth Research, Singapore, Singapore
      name:Department of Clinical Research, Singapore General Hospital, Singapore, Singapore
      name:Population Genetics, Genome Institute of Singapore, Singapore, Singapore
      name:Department of Clinical Research, Singapore General Hospital, Singapore, Singapore
      name:Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands
      name:Department of Clinical Research, Singapore General Hospital, Singapore, Singapore
      name:Department of Clinical Research, Singapore General Hospital, Singapore, Singapore
      name:Knowledge Discovery Department, Institute for Infocomm Research, Singapore, Singapore
      name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
      name:Department of Health Screening, Singapore General Hospital, Singapore, Singapore
      name:National Neuroscience Institute, Singapore, Singapore
      name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
      name:SingHealth Research, Singapore, Singapore
      name:Department of Neurology, Singapore General Hospital, Singapore, Singapore
      name:SingHealth Research, Singapore, Singapore
      name:Population Genetics, Genome Institute of Singapore, Singapore, Singapore
      name:Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-yuan, Taiwan
      name:Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands
      name:Population Genetics, Genome Institute of Singapore, Singapore, Singapore
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