title: Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families.
abstract: To investigate the pathophysiology of Leber's hereditary optic neuropathy (LHON), a cohort of 1164 Han Chinese subjects with LHON were screened for ND1 G3460A mutation. A total of 295 subjects from 16 Han Chinese families carrying the G3460A mutation underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The incidence of G3460A mutation was 1.4% in this cohort of Chinese subjects with LHON. Twenty-seven (20 males/7 females) of 109 matrilineal relatives among 10 Chinese pedigrees carrying this mutation exhibited a wide range of severity and age-at-onset in visual impairment. Penetrances of optic neuropathy ranged from 7.1% to 50%, with the average of 24.5%. The age-at-onset of 27 affected matrilineal relatives varied from 10 to 40 years, with the average of 22 years. Molecular analysis identified the homoplasmic G3460A mutation and distinct sets of variants belonging to eight haplogroups. Haplogroup M with G3460A mutation was of higher frequency than those in controls. The penetrances of visual loss in families carrying mitochondrial DNA haplogroups A, B and M were higher than those in other families. Furthermore, haplogroup-specific variants tRNA(Ser(AGY)) A12223G, tRNA(Thr) G15927A and tRNA(Glu) A14693G may enhance the penetrance of visual loss in these families. The G3460A mutation occurred through recurrent origins and founder events in Chinese population. Mitochondrial modifiers may modulate the penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the G3460A mutation. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.
authors.affiliation: Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: 1] Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China [2] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [3] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Xingtai Eye Hospital, Xingtai, Hebei, China.
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiangjuan
authors.initials: X
authors.lastname: Meng
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Sai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
authors.forename: Qi-Ping
authors.initials: QP
authors.lastname: Wei
authors.affiliation: Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: 1] School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China [2] Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin Mo
authors.affiliation: Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D044466:Asian People / Q000235:genetics; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D003941:Diagnostic Techniques, Ophthalmological; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000201:enzymology* / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D012335:RNA, Ribosomal / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; D009245:NADH Dehydrogenase; C515075:NADH dehydrogenase subunit 1, human