Pingping Jiang1, Min Liang2, Juanjuan Zhang3, Yinglong Gao4, Zheyun He4, Han Yu4, Fuxin Zhao5, Yanchun Ji6, Xiaoling Liu5, Minglian Zhang7, Qun Fu8, Yi Tong9, Yanhong Sun10, Xiangtian Zhou5, Taosheng Huang11, Jia Qu5, Min-Xin Guan12. 1. Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China. 2. Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China. 3. Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. 4. Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China. 5. Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China 4School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. 6. Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 7. Department of Ophthalmology, Xingtai Eye Hospital, Xingtai, Hebei, China. 8. Department of Ophthalmology, The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang, Henan, China. 9. School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. 10. Department of Ophthalmology, Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology, Beijing, China. 11. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States. 12. Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China 8Division of Human Genetics, Cincinnati Chi.
Abstract
PURPOSE: To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase. RESULTS: In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls. CONCLUSIONS: These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.
PURPOSE: To investigate the prevalence and spectrum of mitochondrial ND4 mutations in subjects with Leber's hereditary optic neuropathy (LHON). METHODS: A cohort of 1281 Chinese Han probands and 478 control subjects underwent clinical and genetic evaluation, and sequence analysis of mitochondrial (mt) DNA, as well as enzymatic assay of NADH:ubiquinone oxidoreductase. RESULTS: In this cohort, 503 probands had a family history of optic neuropathy and 778 subjects were sporadic cases. Mutational analysis of ND4 gene identified 149 (102 known and 47 novel) variants. The prevalence of known m.11778G>A mutation was 35.36%. Furthermore, we identified the known m.11696G>A and m.11253T>C mutations and five novel putative LHON-associated mutations. These mutations accounted for 2.74% of cases of LHON subjects. By enzymatic assay, we showed a mild decrease in the activity of NADH:ubiquinone oxidoreductase in mutant cell lines carrying only one putative mtDNA mutation. The low penetrance of optic neuropathy and mild biochemical defects in these pedigrees carrying only m.11696G>A mutation and one putative LHON-associated mutation suggested that the mutation(s) is(are) necessary but is(are) itself(themselves) insufficient to produce a visual failure. Moreover, mtDNAs in 169 probands carrying the LHON-associated mutation(s) were widely dispersed among 13 Eastern Asian haplogroups. In particular, the frequencies of haplogroups D, M8, M10, M11, and H in probands carrying the LHON-associated mtDNA mutation(s) were higher than those in Chinese controls. CONCLUSIONS: These results suggested that the ND4 gene is the hot spot for mutations associated with LHON. Thus, these findings may provide valuable information for the further understanding of pathogenic mechanism of LHON.
Authors: Elena Starikovskaya; Sofia Shalaurova; Stanislav Dryomov; Azhar Nazhmidenova; Natalia Volodko; Igor Bychkov; Ilia Mazunin; Rem Sukernik Journal: Cells Date: 2019-12-04 Impact factor: 6.600
Authors: Paulo Maurício do Amôr Divino Miranda; Sueli Matilde da Silva-Costa; Juliane Cristina Balieiro; Marcela Scabello Amaral Fernandes; Rogério Marins Alves; Andrea Trevas Maciel Guerra; Ana Maria Marcondes; Edi Lúcia Sartorato Journal: Mol Vis Date: 2016-08-13 Impact factor: 2.367