Mitochondrial tRNA[sup.Gln] 4394CT Mutation May Contribute to the Clinical Expression of 1555AG-Induced Deafness

• Published in: Genes Vol. 13; no. 10
• Main Authors: Ding, Yu, Teng, Yaoshu, Guo, Qinxian, Leng, Jianhang
• Format: Journal Article
• Language: English
• Published: MDPI AG 01.10.2022
• Subjects: Deafness; Genetic aspects; Health aspects; Mitochondria; Mutation (Biology); Transfer RNA; China
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes13101794

The mitochondrial 1555A>G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A>G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNA[sup.Gln] 4394C>T mutation to the clinical expression of the m.1555A>G mutation. Interestingly, a three-generation family with both the m.1555A>G and m.4394C>T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A>G mutation. At the molecular level, the m.4394C>T mutation resides within a very conserved nucleotide of tRNA[sup.Gln] , which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A>G and m.4394C>T mutations, three patients with only the m.1555A>G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A>G and m.4394C>T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A>G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A>G and m.4394C>T mutations. Thus, our data suggest that the m.4394C>T mutation may play a synergistic role in the m.1555A>G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.