Jie Shuai1, Jian Shi1, Ya Liang2, Fangfang Ji2, Luo Gu3, Zhilan Yuan4. 1. Department of Ophthalmology, the Affiliated Hospital of Nantong University, Nantong, China. 2. Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China. 3. Department of Physiology, Nanjing Medical University, Nanjing, China. 4. Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China. yuanzhilan001@sohu.com.
Abstract
INTRODUCTION: Mutations in mitochondrial DNA (mtDNA) are the most important causes for Leber's hereditary optic neuropathy (LHON). Of these, three primary mtDNA mutations account for more than 90% cases of this disease. However, to date, little is known regarding the relationship between mitochondrial tRNA (mt-tRNA) variants and LHON. AIM: In this study, we aimed to investigate the association between mt-tRNA variants and LHON. METHODOLOGY: One hundred thirty-eight LHON patients lacking three primary mutations (ND1 3460G > A, ND4 11778Gxs > A, and ND6 14484 T > C), as well as 266 controls were enrolled in this study. PCR-Sanger sequencing was performed to screen the mt-tRNA variants. Moreover, the phylogenetic analysis, pathogenicity scoring system, as well as mitochondrial functions were performed. RESULTS: We identified 8 possible pathogenic variants: tRNAPhe 593 T > C, tRNALeu(UUR) 3275C > T, tRNAGln 4363 T > C, tRNAMet 4435A > G, tRNAAla 5587 T > C, tRNAGlu 14693A > G, tRNAThr 15927G > A, and 15951A > G, which may change the structural and functional impact on the corresponding tRNAs, and subsequently lead to a failure in tRNA metabolism. Furthermore, significant reductions in mitochondrial ATP and MMP levels and an overproduction of ROS were observed in cybrid cells containing these mt-tRNA variants, suggesting that these variants may lead to mitochondrial dysfunction which was responsible for LHON. CONCLUSION: Our study indicated that mt-tRNA variants were associated with LHON, and screening for mt-tRNA variants were recommended for early detection, diagnosis, and prevention of maternally inherited LHON.
INTRODUCTION: Mutations in mitochondrial DNA (mtDNA) are the most important causes for Leber's hereditary optic neuropathy (LHON). Of these, three primary mtDNA mutations account for more than 90% cases of this disease. However, to date, little is known regarding the relationship between mitochondrial tRNA (mt-tRNA) variants and LHON. AIM: In this study, we aimed to investigate the association between mt-tRNA variants and LHON. METHODOLOGY: One hundred thirty-eight LHON patients lacking three primary mutations (ND1 3460G > A, ND4 11778Gxs > A, and ND6 14484 T > C), as well as 266 controls were enrolled in this study. PCR-Sanger sequencing was performed to screen the mt-tRNA variants. Moreover, the phylogenetic analysis, pathogenicity scoring system, as well as mitochondrial functions were performed. RESULTS: We identified 8 possible pathogenic variants: tRNAPhe 593 T > C, tRNALeu(UUR) 3275C > T, tRNAGln 4363 T > C, tRNAMet 4435A > G, tRNAAla 5587 T > C, tRNAGlu 14693A > G, tRNAThr 15927G > A, and 15951A > G, which may change the structural and functional impact on the corresponding tRNAs, and subsequently lead to a failure in tRNA metabolism. Furthermore, significant reductions in mitochondrial ATP and MMP levels and an overproduction of ROS were observed in cybrid cells containing these mt-tRNA variants, suggesting that these variants may lead to mitochondrial dysfunction which was responsible for LHON. CONCLUSION: Our study indicated that mt-tRNA variants were associated with LHON, and screening for mt-tRNA variants were recommended for early detection, diagnosis, and prevention of maternally inherited LHON.
Authors: Valerio Carelli; Chiara La Morgia; Maria Lucia Valentino; Piero Barboni; Fred N Ross-Cisneros; Alfredo A Sadun Journal: Biochim Biophys Acta Date: 2009-03-05
Authors: D C Wallace; G Singh; M T Lott; J A Hodge; T G Schurr; A M Lezza; L J Elsas; E K Nikoskelainen Journal: Science Date: 1988-12-09 Impact factor: 47.728