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Yanchun Ji, Pingping Jiang, Min-Xin Guan; Incidence and spectrum of MT-ND1 mutations in Chinese subjects with Leber’s hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6583.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the mitochondrial ND1 mutational incidence and spectrum in Chinese populations with Leber’s hereditary optic neuropathy (LHON).
Genetic evaluation and molecular analysis of mitochondrial (mt)DNA were underwent in a cohort of 1281 Han Chinese subjects with LHON and 478 control subjects. Biochemical characterizations included enzymatic assay of NADH: ubiquinone oxidoreductase, the measurements of the adenosine triphosphate (ATP) production, and generation of reactive oxygen species using lymphoblastoid cell lines derived from putative mutation matrilineal relatives of these families and control subjects.
The study samples exhibited the variable severity of LHON. Mutational analysis of mitochondrial ND1 gene identified 178 (70 missense and 108 silent) variants in these subjects. Of these, 74 subjects carrying one of five known 3460G>A, 3394T>C, 3635G>A, 3733G>A and 3866T>C mutations accounted for 5.78% cases of this cohort, particularly 1.33% for 3460G>A mutation. Twenty-three putative LHON-associated ND1 mutations were identified in 37 subjects. We found that the levels of the activity of complex I and ATP production in the lymphoblastoid cell lines derived from 13 affected individuals carrying one of 13 putative mutations ranged from 23.7% to 37% and from 64.2% to 78.2%, of the mean value measured in the control cell lines. Therefore, these 13 putative mutations may be influenced the phenotype of LHON. Thus, 111 subjects carrying the LHON-associated ND1 mutations accounted for 8.67% cases of this cohort. The low penetrance of optic neuropathy in pedigrees carrying one of 23 putative mutations indicated that the mutation(s) is necessary but itself insufficient to produce a clinical phenotype. Furthermore, mtDNAs in 111 probands carrying the ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, M10, and R in patients carrying the ND1 mutations were higher than those in Chinese controls.
These data demonstrated that the ND1 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.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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