A possible new mtrRNA mutation site for aminoglycoside-induced deafness syndrome.

Abstract

The aminoglycoside group of antibiotics include some of the most powerful agents in the arsenal available for use against gram-negative bacterial infections and include such compounds as gentamycin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin and neomycin. Their primary intracellular site of action has been shown to be the 30S ribosomal subunit, consisting of 21 proteins and a single 16S molecule of RNA, the 16SrRNA molecule. Bacterial resistance to aminoglycosides has been associated with mutations in both the protein subunits and the 16SrRNA. Gentamycin has been advocated as an antibiotic for aggressive treatment of lung infections in Cystic Fibrosis (CF) patients. This same antibiotic is widely applied in a range of other situations. The primary intracellular site of the antimicrobial action of aminoglycosides is the bacterial 30S ribosomal subunit, consisting of 21 proteins and a single 16S RNA molecule. One unfortunate but relatively rare side-effect of these antibiotics is their ototoxicity; deafness is induced in approximately 1 in 10,000 individuals treated with these antibiotics. Another reported side-effect of the aminoglycosides, nephrotoxicity, may be induced by a similar mechanism to that suggested for ototoxicity. There is now considerable evidence that the aminoglycoside-induced deafness is of mitochondrial origin. The human mitochondrial 12S subunit of ribosomal RNA (rRNA) transcribed from mitochondrial DNA (mtDNA) shares more homology with bacterial 16S rRNA than with the human cytosolic 18S rRNA. As reported by Hutchin et al. (1993) and Prezant et al. (1993), the mtDNA of a group susceptible individuals was shown to contain a mutation, corresponding to nucleotide position 1555 of the 12S rRNA sequence. The mutation was shown to exhibit homoplasmic expression—all copies of the mitochondrial gene in the tissues examined contained the mutation. It was proposed that the slight change in the 12SRNA sequence resulting from this mutation was sufficient to alter the nucleic acid conformation to a more “bacterial-like” structure. Since then there have been a number of reports of other mutated 12S rRNA sites which confer susceptibility to aminoglycoside-induced deafness (Table 1) along with one report of a 16S rRNA mutation associated with this syndrome. It is believed that these mutated structures fail to bind appropriately to the (nuclear-encoded) ribosomal protein components of the mitochondrial translation process. It has been proposed that this leads to the formation of stable mismatched aminoacyl-tRNAs in the 70S ribosome, thereby causing misreading of the (mitochondrially-transcribed) mRNA during protein synthesis.