Genetic factors in aminoglycoside toxicity

Ototoxicity is the major irreversible toxicity of aminoglycosides, and occurs both in a dose-dependent and idiosyncratic fashion. The idiosyncratic pathway is presumably due to genetic predispositions, and in 1993 we identified an inherited mutation that predisposes to aminoglycoside ototoxicity, the A1555G mutation in the mitochondrial 12S ribosomal RNA gene. Seventeen-33% of patients with aminoglycoside ototoxicity carry this mutation. In a search for additional susceptibility mutations, a dual strategy of yeast genetics and candidate genes was employed. Through yeast genetics 8 genes that by overexpression prevent aminoglycoside toxicity were identified. The human homologues of these genes may harbor aminoglycoside susceptibility mutations. Another candidate gene is the mitochondrial ribosomal protein S12, which interacts with the ribosomal RNA gene and in bacteria can harbor aminoglycoside resistance mutations. Analysis of this gene in 41 patients with aminoglycoside ototoxicity did not reveal any mutations in the coding regions. However, an Italian family with five maternally related family members who went deaf after aminoglycosides led to the identification of the second susceptibility mutation in the mitochondrial 12S ribosomal RNA gene, delta T961Cn. While these findings have immediate clinical implications for prevention of aminoglycoside-induced ototoxicity, they have not yet led to a clear understanding of the pathophysiology of aminoglycoside toxicity or the development of therapeutic options after the onset of symptoms.