A Molecular basis for human hypersensitivity of aminoglyscoside antibiotics

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 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.

Naturally Occurring Mutations in Human Mitochondrial Pre-tRNASer(UCN) Can Affect the Transfer Ribonuclease Z Cleavage Site, Processing Kinetics, and Substrate Secondary Structure

“…Interestingly, three other naturally occurring mutations after the discriminator (7445U3 G, 7444C3 U, 7443U3 C (40)) were discovered among Mongolian students in a school for the deaf. These mutations were associated with the 1555A3 G polymorphism in small rRNA that causes deafness with use of aminoglycoside antibiotics (53). Although they have not been confirmed to be pathogenesis-associated, the 7444C3 U (7444G3 A) substitution was suggested several years earlier to lead to translational read-through of the COX1 mRNA on the complementary H strand transcript (54).…”

Rapid identification of an A1555G mutation in human mitochondrial DNA implicated in aminoglycoside-induced ototoxicity

“…The mutation was absent in each of 100 American (Usami et al 1997), 400 Mongolian (Pandya et al 1997), and 414 ethnically diverse subjects (Hutchin et al 1993). Of patients with aminoglycoside-induced deafness, all patients from 12 Spanish families who had received aminoglycosides (Estivill et al 1998), 28 of 32 subjects from 5 Japanese families with a history of aminoglycoside-induced hearing loss (Usami et al 1997), yet only 7 of 41 American patients with aminoglycoside-induced hearing loss were found to possess the mutation.…”

Cosegregation of the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside‐induced and nonsyndromic hearing loss

“…Furthermore, the T1095C mutation in the same rRNA has also been shown to be associated with hearing impairment in several genetically unrelated families [Thyagarajan et al, 2002;Zhao et al, 2004b;Li et al, 2005c]. In contrast to those deafness-associated mitochondrial DNA (mtDNA) mutations reported only in a small number of families from different ethnic origins, the homoplasmic A1555G mutation in the highly conserved decoding site of the 12S rRNA has been associated with both aminoglycoside-induced and nonsyndromic hearing loss in many families of different ethnic origins [Prezant et al, 1993;Hutchin et al, 1993;Matthijis et al, 1996;Pandya et al, 1997;Estivill et al, 1998;del Castillo et al, 2003;Li et al, 2004aLi et al, , 2004b2005b;Young et al, 2005]. Matrilineal relatives within families or in other families carrying the A1555G mutation exhibited incomplete penetrance and variable expressivity including severity and age-of-onset in hearing loss [Prezant et al, 1993;Estivill et al, 1998;Li et al, 2004b;Young et al, 2005].…”