Nucleic Acids Research Advance Access originally published online on April 10, 2007
Nucleic Acids Research 2007 35(8):2759-2766; doi:10.1093/nar/gkm189
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Nucleic Acids Research, 2007, Vol. 35, No. 8 2759-2766
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Identification and characterization of OGG1 mutations in patients with Alzheimer's disease
1Graduate Center for Toxicology, 2Department of Pathology & Laboratory Medicine, 3Sanders-Brown Center on Aging, 4Department of Chemistry, University of Kentucky, Lexington, KY, USA, 5College of Life Sciences, Wuhan University, Wuhan, China and 6Laboratory of Population Genetics, National Cancer Institute, Bethesda, MD, USA
*To whom correspondence should be addressed. Tel: +1 859 323 0285; Fax: +1 859 323 1059; Email: lgu0{at}uky.edu
Received January 31, 2007. Revised March 15, 2007. Accepted March 15, 2007.
Patients with Alzheimer's disease (AD) exhibit higher levels of 8-oxo-guanine (8-oxoG) DNA lesions in their brain, suggesting a reduced or defective 8-oxoG repair. To test this hypothesis, this study investigated 14 AD patients and 10 age-matched controls for mutations of the major 8-oxoG removal gene OGG1. Whereas no alterations were detected in any control samples, four AD patients exhibited mutations in OGG1, two carried a common single base (C796) deletion that alters the carboxyl terminal sequence of OGG1, and the other two had nucleotide alterations leading to single amino acid substitutions. In vitro biochemical assays revealed that the protein encoded by the C796-deleted OGG1 completely lost its 8-oxoG glycosylase activity, and that the two single residue-substituted OGG1 proteins showed a significant reduction in the glycosylase activity. These results were consistent with the fact that nuclear extracts derived from a limited number of AD patients with OGG1 mutations exhibited greatly reduced 8-oxoG glycosylase activity compared with age-matched controls and AD patients without OGG1 alterations. Our findings suggest that defects in OGG1 may be important in the pathogenesis of AD in a significant fraction of AD patients and provide new insight into the molecular basis for the disease.
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