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GSK3B polymorphisms alter transcription and splicing in Parkinson's disease
Author(s) -
Kwok John B. J.,
Hallupp Marianne,
Loy Clement T.,
Chan Daniel K. Y.,
Woo Jean,
Mellick George D.,
Buchanan Daniel D.,
Silburn Peter A.,
Halliday Glenda M.,
Schofield Peter R.
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20691
Subject(s) - haplotype , biology , genetics , single nucleotide polymorphism , gsk3b , gsk 3 , allele , exon , odds ratio , genotype , gene , microbiology and biotechnology , phosphorylation , medicine
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