title: Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics.
abstract: BACKGROUND
  Aminoglycoside ototoxicity is one of the common health problems. Mitochondrial 12S rRNA mutations are one of the important causes of aminoglycoside ototoxicity. However, the incidences of 12S rRNA mutations associated with aminoglycoside ototoxicity are less known.
  
  
  METHODS
  A total of 440 Chinese pediatric hearing-impaired subjects were recruited from two otology clinics in the Ningbo and Wenzhou cities of Zhejiang Province, China. These subjects underwent clinical, genetic evaluation and molecular analysis of mitochondrial 12S rRNA. Resultant mtDNA variants were evaluated by structural and phylogenetic analysis.
  
  
  RESULTS
  The study samples consisted of 227 males and 213 females. The age of all participants ranged from 1 years old to 18 years, with the median age of 9 years. Ninety-eight subjects (58 males and 40 females) had a history of exposure to aminoglycosides, accounting for 22.3% cases of hearing loss in this cohort. Molecular analysis of 12S rRNA gene identified 41 (39 known and 2 novel) variants. The incidences of the known deafness-associated 1555A > G, 1494C > T and 1095T > C mutations were 7.5%, 0.45% and 0.91% in this entire hearing-impaired subjects, respectively, and 21.4%, 2% and 2% among 98 subjects with aminoglycoside ototoxicity, respectively. The structural and phylogenetic evaluations showed that a novel 747A > G variant and known 839A > G, 1027A > G, 1310C > T and 1413T > C variants conferred increased sensitivity to aminoglycosides or nonsyndromic deafness as they were absent in 449 Chinese controls and localized at highly conserved nucleotides of this rRNA. However, other variants were polymorphisms. Of 44 subjects carrying one of definite or putative deafness-related 12S rRNA variants, only one subject carrying the 1413T > C variant harbored the 235DelC/299DelAT mutations in the GJB2 gene, while none of mutations in GJB2 gene was detected in other 43 subjects.
  
  
  CONCLUSIONS
  Mutations in mitochondrial 12S rRNA accounted for ~30% cases of aminoglycoside-induced deafness in this cohort. Our data strongly support the idea that the mitochondrial 12S rRNA is the hot spot for mutations associated with aminoglycoside ototoxicity. These data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.
authors.affiliation: Department of Otolaryngology, Ningbo Medical Center, Li Huili Hospital, Ningbo, Zhejiang, China.
authors.forename: Zhisen
authors.initials: Z
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.forename: Bobei
authors.initials: B
authors.lastname: Chen
authors.forename: Guanghua
authors.initials: G
authors.lastname: Peng
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Shasha
authors.initials: S
authors.lastname: Gong
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Chuqin
authors.initials: C
authors.lastname: Zhang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Jianjin
authors.initials: J
authors.lastname: Zhou
authors.forename: Ting
authors.initials: T
authors.lastname: Cai
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010036:Otolaryngology; D012313:RNA / Q000235:genetics; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000235:genetics*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D000072259:Connexin 26; D012313:RNA