Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation |
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| Authors: | Yuhua Zhu Qi Li Zhengyi Chen Yao Kun Lijia Liu Xin Liu Huijun Yuan Suoqiang Zhai Dongyi Han Pu Dai |
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| Institution: | 1. Department of Otolaryngology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China;2. Department of Otolaryngology, Nanjing Children’s Hospital, Jiangsu, China;3. Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary and Department of Otology and Laryngology, Harvard Medical School, Boston, MA, USA;4. Department of Otolaryngology, Fuyang People’s Hospital, Anhui, China;5. Department of Otolaryngology, Mudanjiang First Hospital, Heilongjiang, China;1. Unidade de Xenética, Instituto de Medicina Legal, and Departamento de Anatomía Patolóxica e Ciencias Forenses, Facultad de Medicina, Universidad de Santiago de Compostela, Galicia 15782, Spain;2. Mitochondrial Research Group, Institute of Genetic Medicine, Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK;3. Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa;1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;2. Department of Radiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, China;3. Department of Emergency, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, China;1. Department of Environmental Health Sciences, School of Public Health, University of Minnesota, Rochester, MN;2. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Rochester, MN |
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| Abstract: | Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNAAla T 5628C and tRNATyr A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness. |
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