Abstract
PURPOSE: This study aimed to examine the frequencies of mt-tRNA(Glu) variants in 180 pediatric patients with non-syndromic hearing loss (NSHL) and 100 controls. METHODS: Sanger sequencing was performed to screen for mt-tRNA(Glu) variants. These mitochondrial DNA (mtDNA) pathogenic mutations were further assessed using phylogenetic conservation and haplogroup analyses. We also traced the origins of the family history of probands carrying potential pathogenic mtDNA mutations. Mitochondrial functions including mtDNA content, ATP and reactive oxygen species (ROS) were examined in cells derived from patients carrying the mt-tRNA(Glu) A14692G and CO1/tRNA(Ser(UCN)) G7444A variants and controls. RESULTS: We identified four possible pathogenic variants: m.T14709C, m.A14683G, m.A14692G and m.A14693G, which were found in NSHL patients but not in controls. Genetic counseling suggested that one child with the m.A14692G variant had a family history of NSHL. Sequence analysis of mtDNA suggested the presence of the CO1/tRNA(Ser(UCN)) G7444A and mt-tRNA(Glu) A14692G variants. Molecular analysis suggested that, compared with the controls, patients with these variants exhibited much lower mtDNA copy numbers, ATP production, whereas ROS levels increased (p<0.05 for all), suggesting that the m.A14692G and m.G7444A variants led to mitochondrial dysfunction. CONCLUSION: mt-tRNA(Glu) variants are important risk factors for NSHL.