Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics.
Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics.
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DOI：
10.1186/1479-5876-9-4
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发表时间：
2011-01-04
影响因子：
7.4
通讯作者：
Guan MX
中科院分区：
文献类型：
--
作者：
Shen Z;Zheng J;Chen B;Peng G;Zhang T;Gong S;Zhu Y;Zhang C;Li R;Yang L;Zhou J;Cai T;Jin L;Lu J;Guan MX
氨基糖苷类耳毒性是常见的健康问题之一。线粒体12 SrRNA突变是氨基糖苷类耳毒性的重要原因之一。然而，与氨基糖苷类耳毒性相关的12 S rRNA突变的发生率鲜为人知。从中国浙江省宁波市和温州市的两个耳科诊所共招募了440名中国儿童听力受损受试者。这些受试者接受了临床、遗传评价和线粒体12 S rRNA分子分析。通过结构分析和系统发育分析评价所得mtDNA变异体。研究样本包括227名男性和213名女性。所有参与者的年龄从1岁到18岁不等，中位年龄为9岁。98例受试者（58例男性和40例女性）有氨基糖苷类药物暴露史，占该队列听力损失病例的22.3%。12 S rRNA基因的分子分析鉴定出41个变异体（39个已知变异体和2个新变异体）。1555 A> G、1494 C> T和1095 T> C突变在全部听力受损者中的发生率分别为7.5%、0.45%和0.91%，在98例氨基糖苷类耳毒性患者中的发生率分别为21.4%、2%和2%。结构和系统发育评价表明，一个新的747 A> G变异体和已知的839 A> G，1027 A> G，1310 C> T和1413 T> C变异体赋予对氨基糖苷类或非综合征性耳聋的敏感性增加，因为它们在449名中国对照中不存在，并且定位于该rRNA的高度保守核苷酸。然而，其他变体是多态性的。在44例12 S rRNA基因突变阳性者中，仅1例1413 T> C突变阳性者存在GJB 2基因235 DelC/299 DelAT突变，其余43例均未检测到GJB 2基因突变。线粒体12 S rRNA突变占该队列中氨基糖苷类药物致聋病例的约30%。我们的数据有力地支持了线粒体12 S rRNA是氨基糖苷类耳毒性相关突变的热点的观点。这些数据提供了有价值的信息和技术，以预测哪些人有耳毒性的风险，以提高氨基糖苷类抗生素治疗的安全性，并最终降低耳聋的发病率。
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.
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影响因子：
30.8
作者：
PREZANT, TR;AGAPIAN, JV;FISCHELGHODSIAN, N
通讯作者：
FISCHELGHODSIAN, N
影响因子：
5.2
作者：
Jacobs, HT;Hutchin, TP;Mueller, RF
通讯作者：
Mueller, RF
影响因子：
2
作者：
Chen, Bobei;Sun, Dongmei;Guan, Min-Xin
通讯作者：
Guan, Min-Xin
影响因子：
3.5
作者：
Chen, Jianfu;Yang, Li;Guan, Min-Xin
通讯作者：
Guan, Min-Xin
影响因子：
4.9
作者：
Qian, Yaping;Guan, Min-Xin
通讯作者：
Guan, Min-Xin