G2Cdb::Human Disease report

Disease id
D00000191
Name
Parkinson's disease
Nervous system disease
yes

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001420 GSK3B
glycogen synthase kinase 3 beta
Y (16315267) Polymorphism (P) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (11809160) Dinucleotide polymorphism (DNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (12490535) Dinucleotide polymorphism (DNP) Y
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (11956967) Single nucleotide polymorphism (SNP) N

References

  • GSK3B polymorphisms alter transcription and splicing in Parkinson's disease.

    Kwok JB, Hallupp M, Loy CT, Chan DK, Woo J, Mellick GD, Buchanan DD, Silburn PA, Halliday GM and Schofield PR

    Garvan Institute of Medical Research, University of New South Wales, Barker Street, Randwick, Sydney NSW 2031, Australia.

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.

    Annals of neurology 2005;58;6;829-39

  • Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study.

    Levecque C, Elbaz A, Clavel J, Richard F, Vidal JS, Amouyel P, Tzourio C, Alpérovitch A and Chartier-Harlin MC

    INSERM Unit 508 Institut Pasteur de Lille, 59019 Lille, France.

    Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS) and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of Parkinson's disease (PD). These data suggest a possible involvement of NOS as factors controlling the resistance of the nigral dopaminergic neurons to environmental insults. Therefore, we investigated whether polymorphisms present in these genes could contribute to the risk of developing PD. We carried out a community-based case-control study among subjects enrolled in the Mutualité Sociale Agricole, the French health insurance organization for workers connected to agriculture. Two-hundred and nine PD patients and 488 controls of European (mostly French) ancestry and matched for age, sex and region of residency were included in this study. Associations were observed with polymorphisms present in exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon 29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no association was observed with a polymorphism in exon 18 of nNOS (OR for carriers of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant interaction of the nNOS polymorphisms with current and ever cigarette smoking was found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an involvement of these two genes as new modifier genes in PD.

    Human molecular genetics 2003;12;1;79-86

  • Association analysis for genetic variants of the NMDA receptor 2b subunit (GRIN2B) and Parkinson's disease.

    Tsai SJ, Liu HC, Liu TY, Cheng CY and Hong CJ

    Department of Psychiatry, Veterans General Hospital-Taipei, Taiwan, ROC.

    Recent studies have implicated N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis and treatment of Parkinson's disease (PD). The NMDA receptor is composed of several subunits, of which, the receptor 2b subunit (GRIN2B) is of particular significance for PD. This subunit is found enriched in the basal ganglia, and PD-monotherapy potential has been determined for GRIN2B antagonists. For this study of a sample population consisting of 101 PD patients and 108 controls, we tested the hypothesis that an ACC --> ACT transversion (2664(th) nucleotide of the coding sequence) affecting codon 888 (tyrosine) of GRIN2B confers susceptibility to PD, or relates to the age of onset. Comparing PD patients and controls, the distribution of the GRIN2B genotypes (p = 0.754) and alleles (p = 0.269) did not differ significantly. The onset age was not significantly different comparing the three genotypic groups (p = 0.189). Our negative findings suggest that it is unlikely that the GRIN2B C2664T polymorphism plays a substantial role in conferring susceptibility to PD in the Chinese population. Further studies with other genetic variations of NMDA subunits, relating either to PD or to the therapeutic response for PD, are suggested.

    Journal of neural transmission (Vienna, Austria : 1996) 2002;109;4;483-8

  • 5'-flanking region polymorphism of the neuronal nitric oxide synthase gene with Parkinson's disease in Taiwan.

    Lo HS, Hogan EL and Soong BW

    Department of Neurology, Taiwan Adventist Hospital, Taipei, Taiwan.

    Though the etiology of Parkinson's disease (PD) is unresolved and may be heterogeneous involving both environmental and genetic factors, there are indications that oxidative stress plays an important role in dopaminergic neuronal death. And, it has been reported that inhibition of nitric oxide synthase (NOS) can prevent the destruction of dopaminergic neurons in mammals. To determine if NOS gene polymorphism affects the 5' flanking region that is immediately upstream of the transcription start site lying between the TATA element and CAATT boxes in PD, and differs significantly between patients with PD and normal controls, we studied genetic polymorphism in that region of the neuronal NOS gene in Chinese patients with PD living in Taiwan. The results indicate that the allele size distribution in that region was statistically significantly different between patients with PD and normal.

    Journal of the neurological sciences 2002;194;1;11-3

Literature (4)

Pubmed - human_disease

  • Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study.

    Levecque C, Elbaz A, Clavel J, Richard F, Vidal JS, Amouyel P, Tzourio C, Alpérovitch A and Chartier-Harlin MC

    INSERM Unit 508 Institut Pasteur de Lille, 59019 Lille, France.

    Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS) and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of Parkinson's disease (PD). These data suggest a possible involvement of NOS as factors controlling the resistance of the nigral dopaminergic neurons to environmental insults. Therefore, we investigated whether polymorphisms present in these genes could contribute to the risk of developing PD. We carried out a community-based case-control study among subjects enrolled in the Mutualité Sociale Agricole, the French health insurance organization for workers connected to agriculture. Two-hundred and nine PD patients and 488 controls of European (mostly French) ancestry and matched for age, sex and region of residency were included in this study. Associations were observed with polymorphisms present in exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon 29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no association was observed with a polymorphism in exon 18 of nNOS (OR for carriers of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant interaction of the nNOS polymorphisms with current and ever cigarette smoking was found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an involvement of these two genes as new modifier genes in PD.

    Human molecular genetics 2003;12;1;79-86

  • 5'-flanking region polymorphism of the neuronal nitric oxide synthase gene with Parkinson's disease in Taiwan.

    Lo HS, Hogan EL and Soong BW

    Department of Neurology, Taiwan Adventist Hospital, Taipei, Taiwan.

    Though the etiology of Parkinson's disease (PD) is unresolved and may be heterogeneous involving both environmental and genetic factors, there are indications that oxidative stress plays an important role in dopaminergic neuronal death. And, it has been reported that inhibition of nitric oxide synthase (NOS) can prevent the destruction of dopaminergic neurons in mammals. To determine if NOS gene polymorphism affects the 5' flanking region that is immediately upstream of the transcription start site lying between the TATA element and CAATT boxes in PD, and differs significantly between patients with PD and normal controls, we studied genetic polymorphism in that region of the neuronal NOS gene in Chinese patients with PD living in Taiwan. The results indicate that the allele size distribution in that region was statistically significantly different between patients with PD and normal.

    Journal of the neurological sciences 2002;194;1;11-3

Pubmed - other

  • GSK3B polymorphisms alter transcription and splicing in Parkinson's disease.

    Kwok JB, Hallupp M, Loy CT, Chan DK, Woo J, Mellick GD, Buchanan DD, Silburn PA, Halliday GM and Schofield PR

    Garvan Institute of Medical Research, University of New South Wales, Barker Street, Randwick, Sydney NSW 2031, Australia.

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.

    Annals of neurology 2005;58;6;829-39

  • Association analysis for genetic variants of the NMDA receptor 2b subunit (GRIN2B) and Parkinson's disease.

    Tsai SJ, Liu HC, Liu TY, Cheng CY and Hong CJ

    Department of Psychiatry, Veterans General Hospital-Taipei, Taiwan, ROC.

    Recent studies have implicated N-methyl-D-aspartate (NMDA) receptor dysfunction in the pathogenesis and treatment of Parkinson's disease (PD). The NMDA receptor is composed of several subunits, of which, the receptor 2b subunit (GRIN2B) is of particular significance for PD. This subunit is found enriched in the basal ganglia, and PD-monotherapy potential has been determined for GRIN2B antagonists. For this study of a sample population consisting of 101 PD patients and 108 controls, we tested the hypothesis that an ACC --> ACT transversion (2664(th) nucleotide of the coding sequence) affecting codon 888 (tyrosine) of GRIN2B confers susceptibility to PD, or relates to the age of onset. Comparing PD patients and controls, the distribution of the GRIN2B genotypes (p = 0.754) and alleles (p = 0.269) did not differ significantly. The onset age was not significantly different comparing the three genotypic groups (p = 0.189). Our negative findings suggest that it is unlikely that the GRIN2B C2664T polymorphism plays a substantial role in conferring susceptibility to PD in the Chinese population. Further studies with other genetic variations of NMDA subunits, relating either to PD or to the therapeutic response for PD, are suggested.

    Journal of neural transmission (Vienna, Austria : 1996) 2002;109;4;483-8

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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