Leber's Hereditary Optic Neuropathy Is Associated with the T3866C Mutation in MitochondrialND1Gene in Three Han Chinese Families

Abstract

,4,5 PURPOSE. To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON).METHODS. Seventy-one subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included the measurements of the rates of endogenous, substratedependent respirations, the adenosine triphosphate (ATP) production and generation of reactive oxygen species using lymphoblastoid cell lines derived from five affected matrilineal relatives of these families and three control subjects. RESULTS.Ten of 41 matrilineal relatives exhibited variable severity and age at onset of optic neuropathy. The average age at onset of optic neuropathy in matrilineal relatives of the three families was 5, 11, and 24 years, respectively. Molecular analysis identified the ND1 T3866C (I187T) mutation and distinct sets of polymorphisms belonging to the Eastern Asian haplogroups D4a, M10a, and R, respectively. The I187T mutation is localized at the highly conserved isoleucine at a transmembrane domain of the ND1 polypeptide. The marked reductions in the rate of endogenous, malate/glutamatepromoted and succinate/glycerol-3-phosphate-promoted respiration were observed in mutant cell lines carrying the T3866C mutation. The deficient respiration is responsible for the reduced ATP synthesis and increased generation of reactive oxygen species.CONCLUSIONS. Our data convincingly show that the ND1 T3866C mutation leads to LHON. This mutation may be insufficient to produce a clinical phenotype. Other modifier factors may contribute to the phenotypic manifestation of the T3866C mutation. The T3866C mutation should be added to the list of inherited factors for molecular diagnosis of LHON. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON. (Invest Ophthalmol Vis Sci.

MitochondrialND1Variants in 1281 Chinese Subjects With Leber's Hereditary Optic Neuropathy

“…In the present investigation, 15 mutant cell lines carrying only one putative mutation(s) exhibited mild decreases in the activity of complex I, ranging from 23.7% to 37%. These data were in good agreement with the observation that there were 27%-40% reductions in NADH dehydrogenase-dependent 15,16,[47][48][49][50] However, the low penetrance of optic neuropathy and mild biochemical defects in these Chinese pedigrees carrying only one putative LHON mutation suggest that the mutation(s) is (are) necessary but is (are) itself (themselves) insufficient to produce a clinical phenotype. Therefore, the nuclear modifiers, or environmental factors, may play a role in the phenotypic manifestation of the mtDNA mutation(s).…”

“…16,42 Furthermore, the m.3866T>C mutation was presented more in Asian than in European patients with LHON. 6,15,43 Therefore, these known LHON-associated MT-ND1 mutations accounted for 2.81% cases of this cohort (1.33% in only m.3460G>A mutation, 0.86% in only m.3635G>A mutations, 0.55% in m.3866T>C mutation, and 0.08% in m.3733G>A mutation). …”

“…23 The homoplasmy of the m.3460G>A, m.3635G>A, m.3733G>A, and m.3866T>C mutations in these subjects was determined as detailed previously. [15][16][17]19,24,25 The allelic frequencies in the MT-ND1 gene in 478 Chinese control subjects were determined by direct sequencing of PCR products as described above. For defining the mitochondrial haplogroups, fragments spanning the D-loop region were PCR amplified by using oligodeoxynucleotides corresponding to mtDNA at positions 15,811 to 775, from 28 probands carrying the m.3394T>C mutation.…”

“…The known primary mutations were the m.3460G>A (17 subjects), m.3635G>A (11 patients), m.3866T>C (7 individuals), and m.3733G>A (1 proband). [15][16][17][18]32 Furthermore, 38 probands harbored the putative known m.3394T>C mutation. 33,34 All the nucleotide changes were verified by sequence analysis of both strands and appeared to be homoplasmy.…”

“…The previous investigations examined the entire mtDNA sequences of 16 subjects carrying the m.3460G>A mutation, 9 subjects carrying the m.3635G>A mutation, and 3 subjects carrying the m.3866T>C mutation. 15,16,28 In the present investigation, we performed the sequence analysis of entire mtDNA genomes from additional eight probands …”