title: Prevalence of Mitochondrial ND4 Mutations in 1281 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy.
abstract: OBJECTIVE
  To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON).
  
  
  METHODS
  A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase.
  
  
  RESULTS
  In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls.
  
  
  CONCLUSIONS
  These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zheyun
authors.initials: Z
authors.lastname: He
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Han
authors.initials: H
authors.lastname: Yu
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Xingtai Eye Hospital, Xingtai, Hebei, China.
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Fu
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China 8Division of Human Genetics, Cincinnati Chi.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D015995:Prevalence; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase