Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C (MT-ND6) mutation in Chinese families |
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Authors: | Juanjuan Zhang Fuxin Zhao Qun Fu Min Liang Yi Tong Xiaoling Liu Bei Lin Hui Mi Minglian Zhang Qi-Ping Wei Ling Xue Pingping Jiang Xiangtian Zhou Jun Qin Mo Taosheng Huang Jia Qu Min-Xin Guan |
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Institution: | 1. Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China;2. School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China;3. Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, China;4. Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, China;5. Department of Ophthalmology, Xingtai Eye Hospital, Xingta, Hebei, China;6. Department of Ophthalmology, Beijing University of Chinese Medicine and Pharmacology, Beijing, China;7. Division of Pathology, Cincinnati Children''s Hospital Medical Center, Cincinnati, OH, USA;8. Division of Human Genetics, Cincinnati Children''s Hospital Medical Center, Cincinnati, OH, USA |
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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. |
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