Dataset Information

Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss.

ABSTRACT: In this report, we investigated the frequency and spectrum of mitochondrial 12S rRNA variants in a large cohort of 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mutational analysis of 12S rRNA gene in these subjects identified 68 (54 known and 14 novel) variants. The frequencies of known 1555A>G and 1494C>T mutations were 3.96% and 0.18%, respectively, in this cohort with nonsyndromic and aminoglycoside-induced hearing loss. Prevalence of other putative deafness-associated mutation at positions 1095 and 961 were 0.61% and 1.7% in this cohort, respectively. Furthermore, the 745A>G, 792C>T, 801A>G, 839A>G, 856A>G, 1027A>G, 1192C>T, 1192C>A, 1310C>T, 1331A>G, 1374A>G and 1452T>C variants conferred increased sensitivity to ototoxic drugs or nonsyndromic deafness as they were absent in 449 Chinese controls and localized at highly conserved nucleotides of this rRNA. However, other variants appeared to be polymorphisms. Moreover, 65 Chinese subjects carrying the 1555A>G mutation exhibited bilateral and sensorineural hearing loss. A wide range of severity, age-of-onset and audiometric configuration was observed among these subjects. In particular, the sloping and flat-shaped patterns were the common audiograms in individuals carrying the 1555A>G mutation. The phenotypic variability in subjects carrying these 12S rRNA mutations indicated the involvement of nuclear modifier genes, mitochondrial haplotypes, epigenetic and environmental factors in the phenotypic manifestation of these mutations. Therefore, our data demonstrated that mitochondrial 12S rRNA is the hot spot for mutations associated with aminoglycoside ototoxicity.

SUBMITTER: Lu J

PROVIDER: S-EPMC2874659 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss.

Lu Jianxin J Li Zhiyuan Z Zhu Yi Y Yang Aifen A Li Ronghua R Zheng Jing J Cai Qin Q Peng Guanghua G Zheng Wuwei W Tang Xiaowen X Chen Bobei B Chen Jianfu J Liao Zhisu Z Yang Li L Li Yongyan Y You Junyan J Ding Yu Y Yu Hong H Wang Jindan J Sun Dongmei D Zhao Jianyue J Xue Ling L Wang Jiying J Guan Min-Xin MX

Mitochondrion 20100125 4

In this report, we investigated the frequency and spectrum of mitochondrial 12S rRNA variants in a large cohort of 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mutational analysis of 12S rRNA gene in these subjects identified 68 (54 known and 14 novel) variants. The frequencies of known 1555A>G and 1494C>T mutations were 3.96% and 0.18%, respectively, in this cohort with nonsyndromic and aminoglycoside-induced hearing loss. Prevalence of other pu ...[more]

PMID: 20100600

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Project description: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.

Project description:BackgroundHearing loss is caused by several environmental and genetic factors and the proportion attributed to inherited causes is assumed at 50?~?60% . Mutations in GJB2 and mitochondrial DNA (mtDNA) 12S rRNA are the most common molecular etiology for nonsyndromic sensorineural hearing loss (NSHL). The mutation spectra of these genes vary among different ethnic groups.MethodsTo add the molecular etiologic information of hearing loss in the Chinese population, a total of 658 unrelated patients with NSHL from Jiangsu Province of China were selected for mutational screening including GJB2 and mtDNA 12S rRNA genes using PCR and DNA sequencing technology. As for controls, 462 normal-hearing individuals were collected.ResultsA total of 9 pathogenic mutations in the GJB2 and 7 pathogenic mutations in the 12S rRNA gene were identified. Of all patients, 70 had monoallelic GJB2 coding region mutation in the heterozygous state, 94 carried two confirmed pathogenic mutations including 79 homozygotes and 15 compound heterozygotes. The 235delC appears to be the most common deafness-causing GJB2 mutation (102/658, 15.50% ). No mutations or variants in the GJB2 exon1 and basal promoter region were found. In these patients, 4 subjects carried the m.1494C?>?T mutation (0.61% ) and 39 subjects harbored the m.1555A?>?G mutation (5.93% ) in mtDNA 12S rRNA gene. A novel sequence variant at m.1222A?>?G in the 12S rRNA gene was identified, which could alter the secondary structure of the 12S rRNA.ConclusionThe mutation spectrum and prevalence of GJB2 and mtDNA 12S rRNA genes in Jiangsu population are similar to other areas of China. There are in total 31.46% of the patients with NSHL carry deafness-causing mutation in GJB2 or mtDNA 12S rRNA genes. Mutation in GJB2 gene is the most common factor, mtDNA 12S rRNA also plays an important part in the pathogenesis of hearing loss in Jiangsu Province areas. The m.1222A?>?G was found to be a new candidate mutation associated with hearing loss. Our results indicated the necessity of genetic screening for mutations of these genes in Jiangsu patients with NSHL.

Project description:Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of non-syndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systematic and extended mutational screening of GJB2 gene in 1067 Han Chinese subjects with non-syndromic hearing loss, and the resultant GJB2 variants were evaluated by phylogenetic, structural and bioinformatic analysis. A total of 25 (23 known and 2 novel) GJB2 variants were identified, including 6 frameshift mutations, 1 nonsense mutation, 16 missense mutations and 2 silent mutations. In this cohort, c.235delC is the most frequently observed pathogenic mutation. The phylogenetic, structural and bioinformatic analysis showed that 2 novel variants c.127G>T (p.V43L), c.293G>C (p.R98P) and 2 known variants c. 107T>C (p.L36P) and c.187G>T (p.V63L) are localized at highly conserved amino acids. In addition, these 4 mutations are absent in 203 healthy individuals, therefore, they are probably the most likely candidate pathogenic mutations. In addition, 66 (24 novel and 42 known) genotypes were identified, including 6 homozygotes, 20 compound heterozygotes, 18 single heterozygotes, 21 genotypes harboring only polymorphism(s) and the wild type genotype. Among these, 153 (14.34%) subjects were homozygous for pathogenic mutations, 63 (5.91%) were compound heterozygotes, and 157 (14.71%) carried single heterozygous mutation. Furthermore, 65.28% (141/216) of these cases with two pathogenic mutations exhibited profound hearing loss. These data suggested that mutations in GJB2 gene are responsible for approximately 34.96% of non-syndromic hearing loss in Han Chinese population from Zhejiang Province in eastern China. In addition, our results also strongly supported the idea that other factors such as alterations in regulatory regions, additional genes, and environmental factors may contribute to the clinical manifestation of deafness.

Dataset Information

Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss.

Publications

Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss.

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