Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity.
The mitochondrial 12S 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 the highly conserved decoding region of the 12S rRNA have been associated with hearing loss worldwide. In particular, these two mutations account for a significant number of cases of aminoglycoside ototoxicity. The 1555A>G or 1494C>T mutation is expected to form a novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the human mitochondrial ribosomes more bacteria-like and alter binding sites for aminoglycosides. As a result, 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 A1555G or 1494C>T mutation. 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 12S rRNA 1555A>G and 1494C>T mutations. Therefore, these data provide valuable information and technology: (1) to predict which individuals are at risk for ototoxicity; (2) to improve the safety of aminoglycoside antibiotic therapy; and (3) eventually to decrease the incidence of hearing loss.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. min-xin.guan@cchmc.org
Min-Xin
MX
Guan
D000617:Aminoglycosides / Q000737:chemistry / Q000633:toxicity*; D002240:Carbohydrate Sequence; D034381:Hearing Loss / Q000139:chemically induced*; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D017720:Molecular Epidemiology; D008969:Molecular Sequence Data; D009154:Mutation; D012335:RNA, Ribosomal / Q000235:genetics*
D000617:Aminoglycosides; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S