A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity

The A1555 G mutation in mitochondrial 12S rRNA has been found to be associa ted with non-syndromic deafness and aminoglycoside-induced deafness. The se nsitivity to the aminoglycoside paromomycin has been analyzed in lymphoblas toid cell lines derived from five deaf individuals and five hearing individ uals from an Arab-Israeli family carrying the A1555G mutation, and three ma rried-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling tim e (DT) in the control cell lines, produced higher average DT increases (49 and 47%) in the A1555G mutation-carrying cell lines derived from symptomati c and asymptomatic individuals, respectively. The ratios of translation rat es in the presence and absence of paromomycin, which reflected the effect o f the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals (b y 30 and 28% on average, respectively), compared with the ratios in the con trol cell lines, These ratios showed, in both groups of mutant cell lines, a significant negative correlation with the ratios of DTs in the presence a nd absence of the antibiotic. These results have provided the first direct evidence that the mitochondrial 12S rRNA carrying the A1555G mutation is th e main target of aminoglycosides, They suggest that these antibiotics exert their detrimental effect through an alteration of mitochondrial protein sy nthesis, which exacerbates the inherent defect caused by the mutation, redu cing the overall translation rate down to and below the minimal level requi red for normal cellular function (40-50%).