Novel mtDNA mutations and oxidative phosphorylation dysfunction in RussianLHON families

Leber's hereditary optic neuropathy (LHON) is characterized by maternally t ransmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute p olypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nu cleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known a s "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and bioche mical analysis of five Russian families from the Novosibirsk region of Sibe ria manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete se quence analysis of proband mtDNA in the other two families has revealed nov el complex I mutations at nps 3635A and 4640C, respectively. These mutation s are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybri ds demonstrated a respiration defect with complex-I-linked substrates, alth ough the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russi a is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression.