A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity.
The A1555 G mutation in mitochondrial 12S rRNA has been found to be associated with non-syndromic deafness and aminoglycoside-induced deafness. The sensitivity to the aminoglycoside paromomycin has been analyzed in lymphoblastoid cell lines derived from five deaf individuals and five hearing individuals from an Arab-Israeli family carrying the A1555G mutation, and three married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49 and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals (by 30 and 28% on average, respectively), compared with the ratios in the control cell lines. These ratios showed, in both groups of mutant cell lines, a significant negative correlation with the ratios of DTs in the presence and absence of the antibiotic. These results have provided the first direct evidence that the mitochondrial 12S rRNA carrying the A1555G mutation is the main target of aminoglycosides. They suggest that these antibiotics exert their detrimental effect through an alteration of mitochondrial protein synthesis, which exacerbates the inherent defect caused by the mutation, reducing the overall translation rate down to and below the minimal level required for normal cellular function (40-50%).
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. guar6n@chmcc.org
M X
MX
Guan
N
N
Fischel-Ghodsian
G
G
Attardi
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018912:Arabs; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003638:Deafness / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007557:Israel; D008297:Male; D010303:Paromomycin / Q000494:pharmacology*; D010375:Pedigree; D012313:RNA / Q000187:drug effects*; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D010303:Paromomycin; D012313:RNA