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The hOGG1 Ser326Cys polymorphism and Huntington's disease
Authors:Fabio Coppedè  Francesca Migheli  Roberto Ceravolo  Elisa Bregant  Anna Rocchi  Lucia Petrozzi  Elisa Unti  Renata Lonigro  Gabriele Siciliano  Lucia Migliore
Institution:1. Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy;2. Department of Human and Environmental Sciences, University of Pisa, Italy;3. Department of Biomedical and Technological Sciences, University of Udine, Udine, Italy
Abstract:Increasing evidence supports a role for oxidative DNA damage and impaired DNA repair mechanisms in the pathogenesis of age related neurodegenerative diseases. Within this context there is a current interest in the understanding of the role played by polymorphisms of DNA repair genes in the inter-individual risk to develop neurodegenerative pathologies, as well as in the onset and the progression of disease symptoms. Particularly, somatic CAG repeat expansion of the gene encoding for huntingtin has been observed in tissues of patients affected by Huntington's disease (HD), including blood and brain. Recent evidence suggests that somatic CAG repeat expansion in HD cells might contribute to disease age at onset and is mediated by the DNA repair OGG1 enzyme, during the removal of 8-oxoguanine (8-oxoG) from the DNA. There is also evidence that the expression of hMTH1, which removes 8-oxoG from the nucleotide pool, protects mice from HD-like symptoms, and progenitor striatal cells from the toxic effects of the mutant huntingtin. The hOGG1 Ser326Cys polymorphism results in reduced OGG1 activity and increased 8-oxoG formation. In the present study, performed on blood DNA from 91 HD subjects, we observed that bearers of the mutant Cys326 allele (Ser326Cys + Cys326Cys) tend to have an increased number of CAG repeats of the expanded HD allele (P = 0.049); moreover bearers of at least one copy of the mutant Cys326 allele, mainly heterozygous subjects, showed a significant (P = 0.041) earlier disease onset than Ser326Ser wild-type individuals, suggesting a possible role of the hOGG1 Ser326Cys polymorphism in HD phenotype.
Keywords:Huntington's disease (HD)  CAG repeat  OGG1  hOGG1 Ser326Cys polymorphism  HD age at onset
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