| Title | Interaction of aminoglycosides with human mitochondrial 12S ribosomal RNA carrying the deafness-associated mutation. | | Author(s) | Qian Y, Guan MX | | Institution | Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. | | Source | Antimicrob Agents Chemother 2009 Aug 17. | | Abstract | Mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside and nonsyndromic hearing loss. Here, we employed a RNA-directed chemical modification approach to understand pathogenesis of aminoglycoside-induced hearing loss. The patterns of chemical modifications in the RNA oligonucleotides carrying the A1555G mutation by dimethyl sulphate were distinct from those of wild-type version, in the presence of aminoglycosides. I n the RNA analogue carrying the A1555G mutation, the reduced reactivity towards DMS occurred in the bases G1555 as well as C1556 and A1553 in the presence of paromomycin, neomycin, gentamicin, kanamycin, tobramycin and streptomycin. In particular, the base G1555 exhibited the marked but similar levels of protection in the presence of 0.1 microM to 100 microM of neomycin, gentamicine and kanamycin. By contrast, the levels of protection in the base G1555 appeared to be correlated with the concentration of paromycin, tobramycin, and steptomycin. Furthermore, the increasing reactivities toward these probes in the presence of these aminoglycosides were observed in the bases A1492, C1493, C1494 and A1557 in the RNA analogue carrying the A1555G mutation. These data suggested that the A1555G mutation altered binding properties of aminoglycosides at the A-site of 12S rRNA and led to local conformation changes in the 12S rRNA carrying the A1555G mutation. The interaction between aminoglycosides and 12S rRNA carrying the A1555G mutation provides new insight into pathogenesis of aminoglycoside ototoxicity. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19687236 |
|
