Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder due to three frequent mtDNA mutations affecting complex I and leading to retinal ganglion cells degeneration and optic atrophy. Penetrance is incomplete, even when the mtDNA mutation is homoplasmic. The modifying role of nuclear genes is assumed to play a role in expressing the pathology. Biochemical investigations in LHON established that bioenergetic inefficiency is combined with increased production of reactive oxygen species. In this study we explored the possible role of the antioxidant machinery as modifier for the expression of LHON. We screened functional polymorphisms in the manganese and copper/ zinc superoxide dismutases (MnSOD, Cu/ZnSOD), in the glutathione peroxidase (GPx) and in the catalase (CAT). We first investigated a large LHON Brazilian/Italian pedigree, comparing affected individuals (n = 26) with unaffected mutation carriers (n = 41). The only significant association (p = 0.036) was found with the MnSOD Ala9Val variant, for which the Ala/Val genotype was most frequent in the affected subjects (65.4%), whereas the Val/Val genotype was most frequent in the carrier individuals (55.3%). Furthermore, we collected 111 Italian LHON unrelated probands and we found that the Ala9Val variant distribution overlapped that found in the Brazilian affected individuals, being significantly different from an equivalent control group of Italians matched for age and sex (p = 0.05). We conclude that only the MnSOD variant seems to modulate the risk of becoming affected. Contrary to the prediction the protective allele is Val, which affects the targeting sequence for mitochondrial import inducing a partial stalling of MnSOD transport, thus lowering the final amount of active enzyme in the matrix. We propose that high MnSOD activity in mitochondria of LHON subjects, which overproduce superoxide, may become deleterious if downstream GPx fails to buffer the excess H2O2.
Maresca A, Tagliavini F, Sangiorgi S, Mendieta L, Amadori M, Salomao S, et al. (2010). Screening of candidate nuclear genes for modifying role in Leber's hereditary optic neuropathy penetrance: A signal from manganese superoxide dismutase. MITOCHONDRION, 10(2), 200-200 [10.1016/j.mito.2009.12.002].
Screening of candidate nuclear genes for modifying role in Leber's hereditary optic neuropathy penetrance: A signal from manganese superoxide dismutase
MARESCA, ALESSANDRA;CARELLI, VALERIO
2010
Abstract
Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder due to three frequent mtDNA mutations affecting complex I and leading to retinal ganglion cells degeneration and optic atrophy. Penetrance is incomplete, even when the mtDNA mutation is homoplasmic. The modifying role of nuclear genes is assumed to play a role in expressing the pathology. Biochemical investigations in LHON established that bioenergetic inefficiency is combined with increased production of reactive oxygen species. In this study we explored the possible role of the antioxidant machinery as modifier for the expression of LHON. We screened functional polymorphisms in the manganese and copper/ zinc superoxide dismutases (MnSOD, Cu/ZnSOD), in the glutathione peroxidase (GPx) and in the catalase (CAT). We first investigated a large LHON Brazilian/Italian pedigree, comparing affected individuals (n = 26) with unaffected mutation carriers (n = 41). The only significant association (p = 0.036) was found with the MnSOD Ala9Val variant, for which the Ala/Val genotype was most frequent in the affected subjects (65.4%), whereas the Val/Val genotype was most frequent in the carrier individuals (55.3%). Furthermore, we collected 111 Italian LHON unrelated probands and we found that the Ala9Val variant distribution overlapped that found in the Brazilian affected individuals, being significantly different from an equivalent control group of Italians matched for age and sex (p = 0.05). We conclude that only the MnSOD variant seems to modulate the risk of becoming affected. Contrary to the prediction the protective allele is Val, which affects the targeting sequence for mitochondrial import inducing a partial stalling of MnSOD transport, thus lowering the final amount of active enzyme in the matrix. We propose that high MnSOD activity in mitochondria of LHON subjects, which overproduce superoxide, may become deleterious if downstream GPx fails to buffer the excess H2O2.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
