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V. Carelli, S. Sangiorgi, M. Mattiazzi, M.L. Valentino, L. Mendieta, A. Berezovsky, S.R. Salomao, R. Belfort, Jr., A.A. Sadun; Screening for Candidate Nuclear Modifying Genes in a Large Brazilian Pedigree with Leber’s Hereditary Optic Neuropathy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1086.
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© ARVO (1962-2015); The Authors (2016-present)
To identify nuclear modifying genes which may influence penetrance and disease expression in a large Leber’s hereditary optic neuropathy (LHON) pedigree from Brazil carrying the 11778/ND4 mutation and haplogroup J.
We used 24 affected individuals and 40 unaffected carriers older than 35 years of age from the same maternal lineage harboring the 11778/ND4 LHON mutation, and 70 off pedigree individuals as control group, to genotype functional polymorphisms in a series of candidate nuclear genes with the potential for modifying factors in LHON. The selected genes were MnSOD (Ala9Val in the mitochondrial targeting sequence), p53 (Arg72Pro), APOE (epsilon 2/3/4), OPA1 (A473G in exon 4), ALR2 (C106>T in the promoter region), and MTHFR (C677>T, A1298>C). Genotype frequencies in the different groups were compared by Chi square test.
Genotype frequencies were significantly different between affected individuals and unaffected carriers for MnSOD (p=0.041) and APOE (p=0.010) when only males were compared. The Val/Val homozygous genotype variant for MnSOD was over–represented in unaffected carriers, while the 3/3 APOE genotype was over–represented in the affected individuals.
Our study reveals a significant difference in genotype polymorphic variants for two nuclear genes comparing affected individuals and unaffected carriers from the same maternal lineage. The involvement of MnSOD as a possible nuclear modifying factor on LHON is in line with the recent finding that mtDNA LHON mutations are associated with increased oxidative stress. The further involvement of APOE is also not surprising, as it is well known as a predisposing factor in neurodegeneration. The current data need to be reproduced in large cohorts of LHON patients of different ethnic origin to be validated.
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