The Association Between Mitochondrial tRNAGlu Variants and Hearing Loss: A Case-Control Study

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. Plain Language Summary:The main aim of our study was to explore the association between the mt-tRNA Glu variants and hearing loss.We found that m.T14709C, m.A14683G, m.A14692G and m.A14693G variants were associated with hearing impairments, these variants localized at extremely conserved nucleotides of mt-tRNA Glu and may result a failure in tRNA metabolism, furthermore, patients with mt-tRNA Glu variants exhibited much lower levels of mtDNA copy number, ATP as compared with controls, whereas ROS increased.As a result, mt-tRNA Glu variants may serve as biomarkers for mitochondrial deafness, and screening for tRNA Glu variants is recommended for early detection and diagnosis of mitochondrial deafness.