Genetic analysis of Japanese pedigrees with Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease, characterized by bilateral optic atrophy mainly in young men. The strict maternal inheritance pattern of LHON can be explained by specific primary mitochondrial (mt) DNA mutations. However, intrafamilial phenotypic variation requires additional pathogenetic factors. Homo- or heteroplasmy of the primary mtDNA mutation, synergistic or antagonistic effects of secondary mtDNA mutations co-existing with the primary mutation, and involvement of an X-linked recessive gene have been postulated to be such factors. In an attempt to determine whether one of the three factors affects LHON expression in Japanese pedigrees, mtDNA analyses by means of RFLP and Southern blot hybridization of PCR products were performed for 22 members in 10 LHON pedigrees, and segregation analysis were conducted for 82 published LHON pedigrees. All of the LHON maternal relatives tested possessed only a homoplasmic mtDNA mutation at position 11778 with none of the secondary mtDNA mutations. Taking into account an extremely high prevalence of the 11778 mutation in Japanese LHON pedigrees (approximately 90%), the results indicated homogeneity of the mitochondrial mutation in Japanese LHON pedigrees. On the other hand, a goodness-of-fit test revealed that the two-locus mitochondrial and X-linked gene control theory accorded well with the characteristic inheritance trait of predominance in males and reduced penetrance with late onset in females. However, the penetrance in heterozygous LHON maternal line females of Japanese pedigrees was about twice as high as that in foreign pedigrees, indicating an ethnic difference in LHON genetics.