Molecular Genetic Analysis Of One Chinese Family With Leber's Heriditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is an eye disorder which generally causes visual loss in young adults with the average onset ages 27-34, but also some individuals affect <1 or >70 years old. Patients often show as acute or subacute visual loss in one eye at first, then develops to both of the eyes with high myopia even visual completely lost. The clinical examination shows that dark spots in the field of vision, Peripheral vessels of optic papilla bend. The mutations of mitochondria DNA were the cause of LHON by molecular genetic testing. Wallance et al. (1988) first found the mutation of a G to A transition at nucleotide 11778 of mtDNA (m.11778G>A). This mutation leads to a substitution of a highly conserved amino acid residue Arginine with a Histidine residue at 340 (p.R340H), and the p.R340H was located on ND4 region. After, another two mutations ND1 m.G3460A (p.G52T) and ND6 m.T14484C (p.M64V) were found. These mutational sites were highly conserved in coenzyme Q of the respiratory chain complex I. The three primary mutations account for over 95 percent of the LHON pedigrees in some countries. Incomplete penetrance and gender bias of the disease expression are two main unsolved problems. Many secondary mutations were discovered and contributed to the penetrance of LHON disease in the pedigree. At present, the pathogenesis of LHON is unclear.To further elucidate molecular basis of LHON in the Chinese population, we have collected and identified a leber's hereditary optic neuropathy pedigree from shandong province in China. The proband was 30 years old male, showed both of eyes with the optic atrophy, some spot-like exudation from macular area in the right eye and the posterior pole of left eye retina was not hemorrhage. This family spans four generations and includes 30 members. Seven patients including five females and two males and fifteen normal members participated in this research. The members of the fourth generation in this family are so young that they are uncertain patients. The family shows incomplete penetrance.In this study, the three primary mtDNA mutations were detected and discovered the ND4 G11778A in proband. At same time, three secondary mutations T3394C, C3497T and C3571T were also found in the proband. The three mutations resulted in p.Y30H, p.A64V and p.L89F of ND1 domain, respectively. The ND4 G11778A and ND1 T3394C, C3497T, C3571T were also in other patients and the proband's mother (asymptomatic). This is first found one primary mtDNA mutation and three secondary mutations in a family. The ND4 G11778A mutation might be the major cause of this Chinese family with LHON, other three secondary mutations T3394C, C3497T and C3571T might be potential modification function and contributed to penetrance and expressivity of LHON in this family. The nonpenetrance mechanisms of LHON by mtDNA mutations were discussed in this study.