title: Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.
abstract: Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρocells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.
authors.affiliation: Divsion of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Department of Clinical Laboratory, The First Affiliated Hospital.|School of Ophthalmology and Optometry.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Chaofan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Qiufen
authors.initials: Q
authors.lastname: He
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Cui
authors.affiliation: School of Ophthalmology and Optometry.|Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Beijing University of Chinese Medicine and Pharmacology, Beijing 100029, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan 45300, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, OH 45229, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Divsion of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China gminxin88@zju.edu.cn.|Institute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Joining Institute of Genetics and Genomic Medicine between Zhejiang University and University of Toronto, Hangzhou, Zhejiang 310058, China.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics; D005260:Female; D060045:Genes, Modifier / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I