Mitochondrial DNA mutations associated with aminoglycoside ototoxicity

The mitochondrial 12 S rRNA is a hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss. Of those, the homoplasmic 1555A ＞ G and 1494C ＞ T mutations at a highly conserved decoding region of the 12 S rRNA have been associated with hearing loss.These two mutations account for a significant number of cases of aminoglycoside ototoxicity. The 15 5 5 A ＞G or 1494C ＞ T mutation is expected to form novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the human mitochondrial ribosome more bacteria-like, alter binding sites for aminoglycosides, thereby accounting for the fact that the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying one of these mutations.Biochemical characterization demonstrated an impairment of mitochondrial protein synthesis and subsequent defects in respiration in cells carrying the C1494T or A1555G mutation, in the presence or absence of aminoglycosides. Furthermore, a wide range of severity, age-at-onset and penetrance of hearing loss was observed within and among families carrying these mutations. Nuclear modifier genes, mitochondrial haplotypes and aminoglycosides should modulate the phenotypic manifestation of the 12 S rRNA 1555 A ＞ G and 1494C ＞ T mutations. Therefore, these data provide valuable information and technology to predict: ①which individuals are at risk for ototoxicity ; ② to improve the safety of aminoglycoside antibiotic therapy ;③ eventually to decrease the incidence of deafness.. Key words: Aminoglycosides ; Ototoxicity ; Hearing loss ; Mitochondrial DNA mutations ; Modifier factors