title: Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families.
abstract: In this report, we investigated the molecular mechanism underlying Leber's hereditary optic neuropathy (LHON)-associated mitochondrial m.3635G>A (p.S110N, ND1) mutation. A mutational screening of ND1 gene in a cohort of 1070 Han Chinese subjects LHON identified the m.3635G>A mutation in nine Chinese families with suggestively maternally transmitted LHON. Thirty-eight (22 males/16 females) of 162 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. Molecular analysis of their mitochondrial genomes identified the homoplasmic m.3635G>A mutation and distinct sets of polymorphisms belonging to the Asian haplogroups G2a1, R11a, D4, R11a, M7b2, G1a, F1a1, B4, and N9a3, respectively. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from one Chinese family into mtDNA-less (ρ(0)) cells, we showed ~27% decrease in the activity of NADH:ubiquinone oxidoreductase (complex I) in mutant cybrids carrying the m.3635G>A mutation, compared with control cybrids. The respiratory deficiency caused by the m.3635G>A mutation results in decreased efficiency of mitochondrial ATP synthesis. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cybrids. The data provide the direct evidence for the m.3635G>A mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON.
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China; School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Jin
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, Hebei, China.
authors.forename: Shipeng
authors.initials: S
authors.lastname: Xie
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Sun
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Ophthalmology, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
authors.forename: Qi-Ping
authors.initials: QP
authors.lastname: Wei
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: gminxin88@zju.edu.cn.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D044466:Asian People; D005006:Ethnicity; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000453:epidemiology* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human
keywords: Leber's hereditary optic neuropathy; Maternal inheritance; Mitochondria; Mutation; NADH:ubiquinone oxidoreductase