Purpose.: To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families.

Methods.: A cohort of 1218 Han Chinese subjects with LHON and 316 control subjects underwent the clinical and genetic evaluation and molecular analysis of mitochondrial (mt) DNA.

Results.: The age at onset of optic neuropathy in these subjects ranged from 5 to 55 years, with the average of 18 years. Mutational analysis of ND6 gene identified 92 (73 known and 19 novel) variants in these subjects. These variants included 29 (9 novel and 20 known) missense mutations and 63 silence variants. A total of 94 subjects carrying one of the known T14484C, T14502C, and G14459A mutations accounted for 7.7% cases of this cohort, particularly 4.4% for T14484C mutation. Furthermore, eight putative LHON-associated ND6 mutations accounted for 1.1% case of this cohort. Thus, 106 subjects carrying one of ND6 mutations accounted for 8.7% cases of this cohort. Low penetrance of optic neuropathy in pedigrees carrying one of eight putative mutations indicated that the mutation (s) is necessary, but itself insufficient to produce a clinical phenotype. Mitochondrial DNAs in 98 probands carrying the ND6 mutation (s) were widely dispersed among 12 Eastern Asian subhaplogroups. In particular, the occurrences of haplogroups M9, M10, M11, and H2 in patients carrying the ND6 mutations were higher than those in controls.

Conclusions.: These data further support that the ND6 gene is the hot spot for mutations associated with LHON. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of LHON.