title: Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C (MT-ND6) mutation in Chinese families.
abstract: Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation.
authors.affiliation: Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China; School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.forename: Qun
authors.initials: Q
authors.lastname: Fu
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.forename: Bei
authors.initials: B
authors.lastname: Lin
authors.forename: Hui
authors.initials: H
authors.lastname: Mi
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.forename: Qi-Ping
authors.initials: QP
authors.lastname: Wei
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D002681:China; D005260:Female; D054629:Genome, Mitochondrial; D006239:Haplotypes; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber; D010375:Pedigree; D010641:Phenotype; D010802:Phylogeny
keywords: Chinese; Haplogroup; Leber's hereditary optic neuropathy; Mitochondrial DNA mutation; ND6; Penetrance