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

206 Citations (Scopus)

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

Fingerprint

Antibiotics
Aminoglycosides
Polymorphism
Hypersensitivity
Anti-Bacterial Agents
Pedigree
Mitochondrial DNA
Ribosomes
Deafness
DNA
Hearing
Human
Audition
Mutation
Three-dimensional
Population
Aminoglycoside-Induced Deafness

ASJC Scopus subject areas

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

Cite this

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

A molecular basis for human hypersensitivity to aminoglycoside antibiotics. / Hutchin, Tim; Haworth, Ian; Higashi, Koichiro; Fischel-Ghodsian, Nathan; Stoneking, Mark; Saha, N.; Arnos, Cathy; Cortopassi, Gino A.

In: Nucleic Acids Research, Vol. 21, No. 18, 11.09.1993, p. 4174-4179.

Research output: Contribution to journalArticle

Hutchin, T, Haworth, I, Higashi, K, Fischel-Ghodsian, N, Stoneking, M, Saha, N, Arnos, C & Cortopassi, GA 1993, 'A molecular basis for human hypersensitivity to aminoglycoside antibiotics', Nucleic Acids Research, vol. 21, no. 18, pp. 4174-4179.
Hutchin T, Haworth I, Higashi K, Fischel-Ghodsian N, Stoneking M, Saha N et al. A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Research. 1993 Sep 11;21(18):4174-4179.
Hutchin, Tim ; Haworth, Ian ; Higashi, Koichiro ; Fischel-Ghodsian, Nathan ; Stoneking, Mark ; Saha, N. ; Arnos, Cathy ; Cortopassi, Gino A. / A molecular basis for human hypersensitivity to aminoglycoside antibiotics. In: Nucleic Acids Research. 1993 ; Vol. 21, No. 18. pp. 4174-4179.
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