GSK3B polymorphisms alter transcription and splicing in Parkinson's disease
Identifieur interne : 001491 ( Main/Exploration ); précédent : 001490; suivant : 001492GSK3B polymorphisms alter transcription and splicing in Parkinson's disease
Auteurs : John B. J. Kwok [Australie] ; Marianne Hallupp [Australie] ; Clement T. Loy [Australie] ; Daniel K. Y. Chan [Australie] ; Jean Woo [République populaire de Chine] ; George D. Mellick ; Daniel D. Buchanan ; Peter A. Silburn ; Glenda M. Halliday [Australie] ; Peter R. Schofield [Australie]Source :
- Annals of Neurology [ 0364-5134 ] ; 2005-12.
Abstract
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‐3β 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 (GSKΔexon9+11). Increased levels of GSKΔexon9+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 GSKΔexon9+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. Ann Neurol 2005;58:829–839
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DOI: 10.1002/ana.20691
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We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase‐3β 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 (GSKΔexon9+11). Increased levels of GSKΔexon9+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 GSKΔexon9+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. Ann Neurol 2005;58:829–839</div></front></TEI><affiliations><list><country><li>Australie</li><li>République populaire de Chine</li></country><settlement><li>Sha Tin</li><li>Sydney</li></settlement><orgName><li>Université chinoise de Hong Kong</li></orgName></list><tree><noCountry><name sortKey="Buchanan, Daniel D" sort="Buchanan, Daniel D" uniqKey="Buchanan D" first="Daniel D." last="Buchanan">Daniel D. Buchanan</name><name sortKey="Mellick, George D" sort="Mellick, George D" uniqKey="Mellick G" first="George D." last="Mellick">George D. 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Halliday</name><name sortKey="Hallupp, Marianne" sort="Hallupp, Marianne" uniqKey="Hallupp M" first="Marianne" last="Hallupp">Marianne Hallupp</name><name sortKey="Kwok, John B J" sort="Kwok, John B J" uniqKey="Kwok J" first="John B. J." last="Kwok">John B. J. Kwok</name><name sortKey="Loy, Clement T" sort="Loy, Clement T" uniqKey="Loy C" first="Clement T." last="Loy">Clement T. Loy</name><name sortKey="Loy, Clement T" sort="Loy, Clement T" uniqKey="Loy C" first="Clement T." last="Loy">Clement T. Loy</name><name sortKey="Schofield, Peter R" sort="Schofield, Peter R" uniqKey="Schofield P" first="Peter R." last="Schofield">Peter R. Schofield</name><name sortKey="Schofield, Peter R" sort="Schofield, Peter R" uniqKey="Schofield P" first="Peter R." last="Schofield">Peter R. Schofield</name><name sortKey="Schofield, Peter R" sort="Schofield, Peter R" uniqKey="Schofield P" first="Peter R." last="Schofield">Peter R. 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