Frequency of mitochondrial 12S ribosomal RNA variants in an adult cystic fibrosis population

Abstract

In adult cystic fibrosis patient populations, gram-negative bacteria, particularly Pseudomonas aeruginosa, frequently require aggressive therapy including systemic antibiotics, bronchodilators and airway clearance techniques. Aminoglycosides including tobramycin are used frequently to control these chronic airway infections. They, however, cause important nephrotoxic and ototoxic effects that can significantly alter the quality of life. We investigated the genetic predisposition to aminoglycoside ototoxicity in a typical unscreened North American cystic fibrosis population by screening for variants in mitochondrial 12S ribosomal RNA and noted several polymorphisms occurred at higher frequencies than expected and were associated with clinically significant cases of hearing loss. In the population studied, both patients possessing the 1555A>G transition exhibited profound ototoxicity after nontoxic dosing of tobramycin. We also identified new homoplasmic genetic variations in the mitochondrial 12S ribosomal RNA, several of which occurred in highly conserved regions of the gene and were present in patients with moderate-to-severe ototoxicity after exposure to aminoglycosides.

Hearing loss in cystic fibrosis

“…The data related to AGS use were collected retrospectively, being therefore susceptible of obliqueness. Another factor to be considered regarding the high prevalence in the group is the genetic predisposition, through mitochondrial mutation (A15555G), which makes patients more susceptible AGS effects, even in weaker doses [22]. New prospective studies will contribute to elucidate the cause of hearing loss in CF.…”

Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis

“…This confers a high risk of ototoxicity when an individual with the mutation is exposed to aminoglycosides. Conrad et al 40 studied an unselected group of 153 adults with CF; 42.2% were found to have “mild” ototoxicity and 8.6% had “moderate to severe ototoxicity”. The investigators sequenced portions of the MT-RNR1 gene of all the patients and found five with polymorphisms previously proposed as mutations associated with hearing impairment; three of these patients had hearing impairment, which was severe in two cases.…”

PharmGKB summary

“…Individuals who carry MT-RNR1 variations such as 1555A>G (rs267606617) and 1494C>T (rs267606619) are highly susceptible to hearing loss after exposure to aminoglycosides, regardless of dose, length of treatment or serum drug levels. The prevalence of the deafness-associated MT-RNR1 variants is unclear and varies by population, but is estimated to be about 1–2% [40–44]. Mitochondrial genes have not been assessed in the populations in the NHLBI Exome Sequencing Project (ESP), 1000 Genomes, or Exome Aggregation Consortium (ExAC) populations.…”

“…identified a cystic fibrosis patient with the 827G allele who had received over 20 lifetime courses of intravenous tobramycin without developing clinically significant hearing loss. However, no audiometric testing was done on this individual [44]. The 827G allele was shown to be absent in unrelated controls or non-matrilineal relatives in multiple studies [70, 73, 74], though it was present at a frequency of 2.9% (6/211) in normal controls in a study by Zhu et al .…”