A molecular basis for human hypersensitivity to aminoglycoside antibiotics

Tim Hutchin, Ian Haworth, Koichiro Higashi, Nathan Fischel-Ghodsian, Mark Stoneking, N. Saha, Cathy Arnos, Gino A Cortopassi

Research output: Contribution to journalArticle

208 Scopus citations

Abstract

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 aminoglycoside-induced deafness (AGD). Here we report that the frequency of a particular mitochondrial DNA polymorphism, 1555G, is associated non-randomly with aminoglycoside-induced 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 aminoglycoside-resistant individuals. We propose a specific molecular mechanism for aminoglycoside hypersensitivity in individuals carrying the 1555G polymorphism, based on the three-dimensional structure of the ribosome, in which the 1555G polymorphism favors aminoglycoside binding sterically, by increasing access to the the ribosome cleft.

Original languageEnglish (US)
Pages (from-to)4174-4179
Number of pages6
JournalNucleic Acids Research
Volume21
Issue number18
StatePublished - Sep 11 1993
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Health, Toxicology and Mutagenesis
  • Toxicology
  • Genetics(clinical)

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  • Cite this

    Hutchin, T., Haworth, I., Higashi, K., Fischel-Ghodsian, N., Stoneking, M., Saha, N., Arnos, C., & Cortopassi, G. A. (1993). A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Research, 21(18), 4174-4179.