Nucleic Acids Research, 1993, Vol. 21, No. 18 4174-4179
© 1993
MOLECULAR BIOLOGY |
A Molecular basis for human hypersensitivity of aminoglyscoside antibiotics
Departments of Molecular Pharmacology and Toxicology 1Pharmaceutical Sciences, University of Southern Califonia Los Angeles, CA 90033, USA 2Department of Otolaryngology, School of Medicine Akita University Akita, Japan 3Department of Peidatrics, Cedars-Sinai Medical Center Los Angeles, CA 90048 4Department of Amthropology, Pennsylvania State University PA 16802 USA 5Department of Pediatrics, National University of Singapore Japan 6Gallaudet University Washington, DC 20002, USA
*To whom correspondence should be addressed
Received July 7, 1993. Revised July 16, 1993. Accepted July 16, 1993.
We have investigated the distribution of mitochondrial DNA polymorphisms in a rare maternally transmitted genetic trait that causes hypersensitivity to aminoglycoside antibiotics, In the hope that a characterization of Its molecular basis might provide a molecular and cellular understanding of amlnoglycoside-induced deafness (AGD). Here we report that the frequency of a particular mitochondrial DNA polymorphism, 1555°, Is associated nonrandomly with aminoglycoslde-lnduced deafness in two 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 individuals surveyed. The 1555G polymorphism occurred In none of 34 amlnoglycoslderesistant Individuals. We propose a specific molecular mechanism for aminoglycoside hypersensitivity in individuals carrying the 1555G polymorphism, based on the three-dimensional structure of the rlbosome, in which the 1555° polymorphism favors aminoglycoside binding sterically, by increasing access to the therlbosome cleft.
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