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V. Carelli, C. Travaglini, M. Sebastiani, M. Mancini, M. L. Valentino, S. R. Salomao, A. A. Sadun, G. d'Amati, C. Giordano; Increase of mtDNA Copy Number Is a Successful Compensatory Strategy in Leber’s Hereditary Optic Neuropathy (LHON). Invest. Ophthalmol. Vis. Sci. 2007;48(13):4412.
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To investigate if increase of mtDNA copy number in LHON is a compensatory strategy, which may influence penetrance. LHON is a maternally inherited blinding disease due to mtDNA point mutations in complex I subunit genes. However, the mtDNA mutation does not explain the male prevalence and the incomplete penetrance observed in LHON.
mtDNA copy number was evaluated by real-time PCR on total DNA extracted from blood. We investigated 35 patients and 57 unaffected mutation carriers belonging to three LHON families, all carrying the 11778/ND4 mutation on a haplogroup J mtDNA background, including the recently described large SOA-BR family from Brazil. As controls (n = 81) we used the spouses from the same families, which do not belong to the mutant maternal lineage.
our results showed that LHON patients had a significant increase in mtDNA content per cell compared to controls (355±145 versus 185±56; p<0,001, values expressed as mean ± standard deviation). In addition, the mtDNA content of the unaffected mutation carriers (564±253) was significantly higher than in the affected individuals (p<0,001). Stratifying the data from the large SOA-BR family by age and sex, a significant dependence of mtDNA copy number from age was observed in the female carriers, with a reduction of mtDNA amount in unaffected women older than 50 years.
our study shows that LHON mutations, which impair mitochondrial respiratory function and enhance oxidative stress, induce mitochondrial biogenesis increasing mtDNA copy number. The efficiency of this compensatory strategy of the cells distinguishes the affected individuals from their maternal relatives, which remain unaffected mutation carriers. Thus, we provide a valuable mechanism to explain variability in penetrance, and clues to identify the nuclear modifying gene/s in LHON, opening an avenue to develop a predictive genetic test on disease risk and new therapeutic strategies.
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