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  • GSK3B Polymorphisms Alter Transcription and Splicing in Parkinson’s Disease

    Author(s)
    Kwok, JBJ
    Hallupp, M
    Loy, CT
    Chan, DKY
    Woo, J
    Mellick, GD
    Buchanan, DD
    Silburn, PA
    Halliday, GM
    Schofield, PR
    Griffith University Author(s)
    Mellick, George
    Year published
    2005
    Metadata
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    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-3 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 (GSKexon9+11). Increased ...
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    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-3 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 (GSKexon9+11). Increased levels of GSKexon9+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 GSKexon9+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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    Journal Title
    Annals of Neurology
    Volume
    58
    Issue
    6
    DOI
    https://doi.org/10.1002/ana.20691
    Copyright Statement
    Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
    Subject
    Clinical sciences
    Neurosciences
    Publication URI
    http://hdl.handle.net/10072/20722
    Collection
    • Journal articles

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