A MOLECULAR-BASIS FOR HUMAN HYPERSENSITIVITY TO AMINOGLYCOSIDE ANTIBIOTICS

We have investigated the distribution of mitochondrial DNA polymorphis ms in a rare maternally transmitted genetic trait that causes hypersen sitivity to aminoglycoside antibiotics, in the hope that a characteriz ation of its molecular basis might provide a molecular and cellular un derstanding of aminoglycoside-induced deafness (AGD). Here we report t hat the frequency of a particular mitochondrial DNA polymorphism, 1555 G, is associated nonrandomly with aminoglycoside-induced deafness in t wo Japanese pedigrees, bringing the frequency of this polymorphism to 5 occurrences in 5 pedigrees of AGD, and in 4 of 78 sporadic cases in which deafness was thought to be the result of aminoglycoside exposure ; both frequencies are significantly different from the occurrence of this mutation in the hearing population, which was 0 in 414 individual s surveyed. The 1555G polymorphism occurred in none of 34 aminoglycosi de-resistant individuals. We propose a specific molecular mechanism fo r aminoglycoside hypersensitivity in individuals carrying the 1555G po lymorphism, based on the three-dimensional structure of the ribosome, in which the 1555G polymorphism favors aminoglycoside binding sterical ly, by increasing access to the the ribosome cleft.