Purpose: To preliminarily examine whether mitochondrial heteroplasmy or synergism of multiple mitochondrial (mt) DNA mutations are related to the symptoms manifested in Japanese pedigrees with Leber's hereditary optic neuropathy (LHON), 90 percent of which have an mtDNA mutation at position 11778 in the NADH dehydrogenase subunit 4 (ND4) gene. This would be a first step toward clarifying why not all individuals with the 11778 mutation are affected in this ethnically unique population.
Methods: Seven ND4 11778 mutant Japanese pedigrees, including 17 maternal line members, were analyzed by restriction fragment length polymorphisms and Southern blot hybridization using mutant and wild-type sequence-specific oligonucleotide probes of leukocyte DNA amplified by polymerase chain reaction.
Results: All of the members, regardless of symptoms, were revealed to possess only the homoplasmic ND4 11778 mutation with no other mtDNA mutation tested. On the other hand, all of the affected individuals were male, and conversely, all of the unaffected were female, except for an 18-year-old male with only peripapillary microangiopathy.
Conclusions: Neither heteroplasmy of the ND4 11778 mutation nor simultaneous mutations reported in the different complex I genes can account for the variation in the clinical phenotype in our series. Taken together with the sex bias in symptom manifestation, the results indirectly suggest that an extramitochondrial factor, such as an X-chromosome-linked gene, possibly contributes to the development of optic atrophy in the Japanese LHON pedigrees tested.