Mitochondrial 12S rRNA A827G mutation is involved in the genetic susceptibility to aminoglycoside ototoxicity Guangqian Xing a,1 , Zhibin Chen a,1 , Qinjun Wei b , Huiqin Tian a , Xiaolu Li a , Aidong Zhou c , Xingkuan Bu a , Xin Cao b, * a Department of Otolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China b Department of Biotechnology, Nanjing Medical University, Nanjing 210029, China c Nanjing City School for Deaf Children, Nanjing 210000, China Received 19 May 2006 Available online 12 June 2006 Abstract 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 anti- biotics 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 unre- lated 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 pen- etrance 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 car- rying 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. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Hearing loss; Inherited; Mitochondrial DNA; 12S rRNA; Mutation; A827G; Chinese; Aminoglycosides Aminoglycoside antibiotics, such as gentamicin, strepto- mycin, kanamycin, and tobramycin, are clinically impor- tant drugs. They are used world-wide for controlling bacteria-related infections, especially in developing coun- tries. However, these drugs may become concentrated in the perilymph and endolymph of the inner ear, potentially leading to ototoxicity [1]. At very high doses, most individ- uals will exhibit toxicity. By contrast, some patients devel- oped aminoglycoside-induced hearing loss after treatment with conventional doses, even a single dose of drug, over a short period. These cases of aminoglycoside ototoxicity may have a genetic predisposition with autosomol domi- nant, autosomal recessive, X-linked, or mitochondrial pat- terns of inheritance [2]. In particular, in familial cases of ototoxic deafness, the aminoglycoside hypersensitivity is usually maternally transmitted, suggesting mitochondrial genome involvement [3]. Mutations in the mitochondrial DNA (mtDNA) have been found to be associated with non-syndromic sensori- neural hearing loss (SNHL) [2,3]. Among the identified non-syndromic deafness-associated mtDNA mutations are A1555G [4,5], T1095C [6,7], C1494T [8], and 961 0006-291X/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2006.05.208 * Corresponding author. Fax: +86 25 8686 2837. E-mail address: caoxin@njmu.edu.cn (X. Cao). 1 These authors contributed equally to this work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 346 (2006) 1131–1135 BBRC