title: Leber's hereditary optic neuropathy is associated with the T3866C mutation in mitochondrial ND1 gene in three Han Chinese Families.
abstract: OBJECTIVE
  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, substrate-dependent 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/glutamate-promoted 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.
authors.affiliation: School of Ophthalmology and Optometry, Wenzhou Medical College, Zhejiang, China.
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.forename: Yaping
authors.initials: Y
authors.lastname: Qian
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.forename: Xianning
authors.initials: X
authors.lastname: Dai
authors.forename: Huihui
authors.initials: H
authors.lastname: Zhou
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
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*; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D050259:Genes, Mitochondrial / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D029242:Optic Atrophy, Hereditary, Leber / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human