LAUSR

Mutations in the mitochondrial tRNAs have been reported to be the important cause of hearing loss. However, only a few cases have been identified thus far and the prevalence of mitochondrial tRNA mutations in hearing-impaired patients remain unclear. Here we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 887 Han Chinese subjects with hearing loss by Sanger sequencing. The systemic evaluation of putative pathogenic variants was further carried out by frequency in controls (<1%), phylogenetic analysis, structural analysisandfunctionalprediction. As a result, a total of 147 variants on 22 tRNA genes were identified. Among these, 39 tRNA mutations (10 pathogenic and 29 likely pathogenic) which absent or present <1% in 773 Chinese controls, localized at highly conserved nucleotides, or changed the modified nucleotides, could have potential structural alterations and functional significance, thereby considered to be deafness-associated mutations. Furthermore, 44 subjects carried one of these 39 pathogenic/likely pathogenic tRNA mutations with a total prevalence of 4.96%. However, the phenotypic variability and incomplete penetrance of hearing loss in pedigrees carrying these tRNA mutations indicate the involvement of modifier factors, such as nuclear encoded genes associated with mitochondrion biogenesis, mitochondrial haplotypes, epigenetic and environmental factors. Thus, our data provide the evidence that mitochondrial tRNA mutations are the important causes of hearing loss among Chinese population. These findings further increase our knowledge on the clinical relevance of tRNA mutations in the mitochondrial genome, and should be helpful to elucidate the pathogenesis of maternal hearing loss.