A molecular basis for human hypersensitivity to aminoglycoside antibiotics.
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 nonrandomly 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.
Hutchin
T
T
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033.
Haworth
I
I
Higashi
K
K
Fischel-Ghodsian
N
N
Stoneking
M
M
Saha
N
N
Arnos
C
C
Cortopassi
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial; D003638:Deafness / Q000139:chemically induced; D004342:Drug Hypersensitivity / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010375:Pedigree; D011110:Polymorphism, Genetic; D012335:RNA, Ribosomal / Q000737:chemistry
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal