Yanchun Ji1, Min Liang2, Juanjuan Zhang3, Ling Zhu4, Zengjun Zhang5, Runing Fu5, Xiaoling Liu6, Minglian Zhang7, Qun Fu8, Fuxin Zhao6, Yi Tong4, Yanhong Sun9, Pingping Jiang1, Min-Xin Guan1. 1. Insitute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Chi. 2. Insitute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 3Department of Clinical Laboratory, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 3. Insitute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. 4. Insitute of Genetics, Zhejiang University and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 5. Department of Clinical Laboratory, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China. 6. School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. 7. Department of Ophthalmology, Hebei Provincial Eye Hospital, Xingtai, Hebei, China. 8. Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, China. 9. Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing, China.
Abstract
PURPOSE: The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls. RESULTS: Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls. CONCLUSIONS: These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.
PURPOSE: The purpose of this study was to investigate the mutational incidence and spectrum of mitochondrial ND1 gene in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Han Chinese probands and 478 control subjects underwent sequence analysis of mitochondrial (mt)DNA. Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. Respiratory complex activities were measured using lymphoblastoid cell lines derived from 25 probands carrying the mtDNA mutation and 3 controls. RESULTS: Mutational analysis identified 178 (70 missense and 108 silent) variants in the MT-ND1 gene. The incidences of known m.3460G>A, m.3635G>A, m.3733G>A, m.3866T>C, and m.3394T>C mutations were 1.33%, 0.86%, 0.08%, 0.55%, and 2.97%, respectively. Fifteen novel putative mutations were identified in 27 probands, translated into 2.1% cases of this cohort. The activity of complex I in mutant cell lines carrying one of putative mutations ranged from 66% to 76% of the average values in control cell lines, whereas activities of complexes II, III, and IV in mutant cells were comparable with those in controls. The low penetrances of optic neuropathy were observed in pedigrees carrying novel putative mutation(s). Moreover, mtDNAs in 101 probands carrying the MT-ND1 mutation(s) were widely dispersed among 15 Eastern Asian haplogroups. In particular, the occurrences of haplogroups M, M9, and M10 in patients carrying the ND1 mutations were higher than those in controls. CONCLUSIONS: These data demonstrated that the MT-ND1 gene is a hot spot for mutations associated with LHON. Our findings may provide valuable information for pathophysiology, management, and genetic counseling of LHON.
Authors: L F Araujo; A T Terra; C T G Sares; C F R Sobreira; E F Faria; R D Machado; A A Rodrigues; V F Muglia; W A Silva; R B Reis Journal: Mol Biol Rep Date: 2018-06-12 Impact factor: 2.316