Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss |
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Authors: | Jianxin Lu Zhiyuan Li Yi Zhu Aifen Yang Ronghua Li Jing Zheng Qin Cai Guanghua Peng Wuwei Zheng Xiaowen Tang Bobei Chen Jianfu Chen Zhisu Liao Li Yang Yongyan Li Junyan You Yu Ding Hong Yu Jindan Wang Dongmei Sun Min-Xin Guan |
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Institution: | 1. Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, OH, United States;2. Department of Pediatrics, University of Maryland, Baltimore, MD, United States;3. Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, United States;4. Department of Pediatrics, Division of Genetics, Stanford University School of Medicine, Stanford, CA, United States;5. Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States;6. Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States;7. Center for Inherited Disorders of Energy Metabolism (CIDEM), University Hospitals Case Medical Center, Cleveland, OH, United States;8. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States;9. Department of Medicine, Case Western Reserve University, Cleveland, OH, United States |
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Abstract: | In this report, we investigated the frequency and spectrum of mitochondrial 12S rRNA variants in a large cohort of 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mutational analysis of 12S rRNA gene in these subjects identified 68 (54 known and 14 novel) variants. The frequencies of known 1555A>G and 1494C>T mutations were 3.96% and 0.18%, respectively, in this cohort with nonsyndromic and aminoglycoside-induced hearing loss. Prevalence of other putative deafness-associated mutation at positions 1095 and 961 were 0.61% and 1.7% in this cohort, respectively. Furthermore, the 745A>G, 792C>T, 801A>G, 839A>G, 856A>G, 1027A>G, 1192C>T, 1192C>A, 1310C>T, 1331A>G, 1374A>G and 1452T>C variants conferred increased sensitivity to ototoxic drugs or nonsyndromic deafness as they were absent in 449 Chinese controls and localized at highly conserved nucleotides of this rRNA. However, other variants appeared to be polymorphisms. Moreover, 65 Chinese subjects carrying the 1555A>G mutation exhibited bilateral and sensorineural hearing loss. A wide range of severity, age-of-onset and audiometric configuration was observed among these subjects. In particular, the sloping and flat-shaped patterns were the common audiograms in individuals carrying the 1555A>G mutation. The phenotypic variability in subjects carrying these 12S rRNA mutations indicated the involvement of nuclear modifier genes, mitochondrial haplotypes, epigenetic and environmental factors in the phenotypic manifestation of these mutations. Therefore, our data demonstrated that mitochondrial 12S rRNA is the hot spot for mutations associated with aminoglycoside ototoxicity. |
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