Mitochondrial 12S rRNA A827G mutation is involved in the genetic susceptibility to aminoglycoside ototoxicity.
We have analyzed the clinical and molecular characterization of a Chinese family with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluations revealed that only those family members who had a history of exposure to aminoglycoside antibiotics subsequently developed hearing loss, suggesting mitochondrial genome involvement. Sequence analysis of the mitochondrial 12S rRNA and tRNA(Ser(UCN)) genes led to the identification of a homoplasmic A827G mutation in all maternal relatives, a mutation that was identified previously in a few sporadic patients and in another Chinese family with non-syndromic deafness. The pathogenicity of the A827G mutation is strongly supported by the occurrence of the same mutation in two independent families and several genetically unrelated subjects. The A827G mutation is located at the A-site of the mitochondrial 12S rRNA gene which is highly conserved in mammals. It is possible that the alteration of the tertiary or quaternary structure of this rRNA by the A827G mutation may lead to mitochondrial dysfunction, thereby playing a role in the pathogenesis of hearing loss and aminoglycoside hypersensitivity. However, incomplete penetrance of hearing impairment indicates that the A827G mutation itself is not sufficient to produce clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Indeed, aminoglycosides may contribute to the phenotypic manifestation of the A827G mutation in this family. In contrast with the congenital or early-onset hearing impairment in another Chinese family carrying the A827G mutation, three patients in this pedigree developed hearing loss only after use of aminoglycosides. This discrepancy likely reflects the difference of genetic backgrounds, either mitochondrial haplotypes or nuclear modifier genes, between two families.
Xing
Guangqian
G
Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Chen
Zhibin
Z
Wei
Qinjun
Q
Tian
Huiqin
H
Li
Xiaolu
X
Zhou
Aidong
A
Bu
Xingkuan
X
Cao
Xin
X
D000617:Aminoglycosides / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000032:analysis*; D050259:Genes, Mitochondrial; D020022:Genetic Predisposition to Disease; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D017354:Point Mutation; D012335:RNA, Ribosomal / Q000032:analysis / Q000235:genetics*
D000617:Aminoglycosides; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S