Identification and characterization of OGG1 mutations in patients with Alzheimer's disease

Abstract

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.

Poly(ADP-ribose) Polymerase 1 (PARP-1) Binds to 8-Oxoguanine-DNA Glycosylase (OGG1)

“…Several OGG1 polymorphisms have been reported and correlate with diseases including cancer and Alzheimer disease (25,26,50,51). Two frequently observed OGG1 polymorphisms include the R229Q and S326C mutations in the C terminus of OGG1 (17,52).…”

Evidence That a Mutation in the MLH1 3′-Untranslated Region Confers a Mutator Phenotype and Mismatch Repair Deficiency in Patients with Relapsed Leukemia

“…Single-strand Conformation Polymorphism and DNA Sequencing-Mutations in the 3Ј-UTR of the MLH1 gene were screened using PCR-based single-strand conformation polymorphism (SSCP) analysis and DNA sequencing, essentially as described (9,10). PCR primers ex19F (CAAA CAGGGAG-GCTTATGA) and ex19R (AAATAA GAAATTATGTTAA-GACACATC) and 3Ј-utrF (CGCGCTCGAGATATGGT-TATTTATGCACTGTGG) and 3ЈutrR (CCCACTACGTGC-AGAGCCT GTGACATGTTCAAGA) were used to amplify part of exon 19 and the upstream sequence of the 3Ј-UTR and the downstream sequences of the 3Ј-UTR (see Fig.…”

“…MSI Analysis-Five standard microsatellite markers from five different chromosomes (CHLC.GGAA4D07, D8S135, MfD257, ACTC, GGAA2E02) were used to determine MSI in AML0805 and AML0606 as described (9,10). Similarly, frameshift mutations in mononucleotide runs in exon 2 of CASPASE-5 and intron 5 of FANCD2 were investigated using the primers and conditions reported elsewhere (11) with minor modifications.…”

“…1A), indicative of MSI (13). Instability was also examined in mononucleotide repeat markers CASPASE-5(A) 10 (Fig. 1B) and FANCD2(T) 10 (Fig.…”

“…Instability was also examined in mononucleotide repeat markers CASPASE-5(A) 10 (Fig. 1B) and FANCD2(T) 10 (Fig. 1C), where a run of 10 adenines and 10 thymines were present in exon 2 of CASPASE-5 and intron 5 of FANCD2, respectively.…”