Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics

Department of Otolaryngology, Ningbo Medical Center, Li Huili Hospital, Ningbo, Zhejiang, China.
Journal of Translational Medicine (Impact Factor: 3.99). 01/2011; 9:4. DOI: 10.1186/1479-5876-9-4
Source: PubMed

ABSTRACT 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.
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.
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.
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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations of mitochondrial DNA are linked to many human diseases. Despite the identification of a large number of variants in the mitochondrially-encoded rRNA (mt-rRNA) genes, the evidence supporting their pathogenicity is, at best, circumstantial. Establishing the pathogenicity of these variations is of major diagnostic importance. Here, we aim to estimate the disruptive effect of mt-rRNA variations on the function of the mitochondrial ribosome. In the absence of direct biochemical methods to study the effect of mt-rRNA variations, we relied on the universal conservation of the rRNA fold to infer their disruptive potential. Our method, named Heterologous Inferential Analysis or HIA, combines conservational information with functional and structural data obtained from heterologous ribosomal sources. Thus, HIA's predictive power is superior to the traditional reliance on simple conservation indexes. By using HIA we have been able to evaluate the disruptive potential for a subset of uncharacterized 12S mt-rRNA variations. Our analysis revealed the existence of variations in the rRNA component of the human mitoribosome with different degrees of disruptive power. In cases where sufficient information regarding the genetic and pathological manifestation of the mitochondrial phenotype is available, HIA data can be used to predict the pathogenicity of mt-rRNA mutations. In other cases, HIA analysis will allow the prioritisation of variants for additional investigation. Eventually, HIA-inspired analysis of potentially pathogenic mt-rRNA variations, in the context of a scoring system specifically designed for these variants, could lead to a powerful diagnostic tool.
    Human Molecular Genetics 10/2013; 23(4). DOI:10.1093/hmg/ddt490 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hearing loss (HL) is a common genetically heterogeneous sensory disorder, occurring in 1 to 3 per 1000 live births. In spite of the extraordinary genetic heterogeneity, variants in GJB2, MT-RNR1, and SLC26A4 genes have been considered as the main reasons of nonsyndromic hearing loss in Chinese population. We developed a rapid multiplex genetic screening system called the SNPscan assay technique which could detect the 115 mutations of the above three genes. This technique is a high-throughput and cost-saving SNP genotyping method. We found that the carrier rate of mutations in the GJB2 gene, MT-RNR1 gene, and SLC26A4 gene was 26.21%, 1.86%, and 25.46% of the patients with nonsyndromic hearing loss, respectively. Using this method, up to 50% of the patients in our study were identified to have hereditary HL caused by mutations in the three genes. It is applicable to not only genetic diagnosis of HL, but also molecular screening of other inherited diseases.
    Genomics 08/2014; 104(4). DOI:10.1016/j.ygeno.2014.07.009 · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetic variations, including mitochondrial mutations, are important contributors to hearing loss, especially in children, and newborn genetic screens for hearing loss mutations are becoming increasingly common. Mitochondrial mutations have been linked with ototoxic responses to common antibiotics, therefore understanding the association of these mutations with hearing loss is of special importance. To address the usefulness of screening for these mutations in a clinical setting, we formed a collaboration of clinicians and geneticists to analyse the association of mitochondrial mutations with non-syndromic hearing loss, including the effect of ethnicity, audiological test methods and aminoglycoside exposure. This survey identified 122 variants in 43 studies that have been assessed for an association with hearing loss, and meta-analysis was performed on clinically relevant subsets. RNA folding and conservation analysis further explored possible relevance of these variants. Among all studies, eight variants were found to have significant associations with hearing loss. A partially overlapping set of six variants had significant association with hearing loss when aminoglycoside exposure was assessed. Five of these variants predictive of sensitivity to aminoglycoside spatially co-localise in an RNA folding model. There was little effect of the audiological test method used to assess hearing loss on the association with the variants. Our results found a small set of studied variants had reproducible association with hearing loss, which will help clarify mutations useful in genetic screens for hearing loss. Several of the aminoglycoside exposure-associated mutations may co-localise on folded 12S rRNA, suggesting a functional association between these loci and aminoglycoside-induced hearing loss. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Medical Genetics 12/2014; 52(2). DOI:10.1136/jmedgenet-2014-102753 · 5.64 Impact Factor

Full-text (4 Sources)

Available from
May 22, 2014