Inherited susceptibility to aminoglycoside ototoxicity: Genetic heterogeneity and clinical implications
Inherited susceptibility to aminoglycoside ototoxicity: Genetic heterogeneity and clinical implications
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DOI：
10.1016/s0196-0709(99)90062-5
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发表时间：
1999-05-01
影响因子：
2.5
通讯作者：
Fischel-Ghodsian, N
中科院分区：
文献类型：
--
作者：
Casano, RAMS;Johnson, DF;Fischel-Ghodsian, N
目的：氨基糖苷类药物诱导的耳毒性似乎在某些个体中具有遗传易感性，线粒体12S核糖体RNA基因中的A1555G突变已被证明是所有常见病例中这种易感性的原因。一个意大利家族有5名成员在氨基糖苷类药物暴露后耳聋，分子分析排除了A1555G突变。本研究的目的是确定aminoglycosides易感性的分子基础，在这个family.Patients和方法：两个姐妹篇和他们的三个孩子开发严重到深刻的高频听力损失aminoglycosides暴露后。从这些个体及其未受影响的亲属的血液中提取DNA，并分析线粒体DNA突变。结果：12S核糖体RNA基因的测序结果显示，在961位有一个胸苷缺失，该突变周围有一个复杂的序列模式。对961突变周围的单个克隆进行测序，结果表明在不同的线粒体molecules.Conclusion中插入了不同数量的胞嘧啶，该家族建立了与线粒体12S核糖体RNA基因中插入的胞嘧啶数量不同的核苷酸961胸苷缺失相关的第二致病突变，可导致氨基糖苷类耳毒性。它证明了在对任何患者给予氨基糖苷类药物前询问家族史的临床意义。此外，对氨基糖苷类药物引起的听力损失的散发患者进行1555和961突变的分子检测是理想的。这种筛查可以显著降低氨基糖苷类药物引起的听力损失的患病率。版权所有（C）1999 W.B.桑德斯公司
Purpose: Aminoglycoside-induced ototoxicity appears to have a genetic susceptibility in some individuals, and the A1555G mutation in the mitochondrial 12S ribosomal RNA gene has been shown to be responsible for this susceptibility in all familiar cases. An Italian family with 5 family members who became deaf after aminoglycoside exposure presented to us, and molecular analysis excluded the A1555G mutation. The purpose of this study is to identify the molecular basis for the aminoglycoside susceptibility in this family.Patients and Methods: Two sisters and three of their children developed severe to profound high-frequency hearing loss after aminoglycoside exposure. DNA was extracted from the blood of these individuals and their unaffected relatives, and analyzed for mitochondrial DNA mutations. The region around nucleotide 961 was also cloned and individual clones were sequenced.Results: Sequencing of the 12S ribosomal RNA gene revealed a thymidine deletion at position 961, with a complex pattern of sequence around this mutation. Sequencing of individual clones around the 961 mutation demonstrated a varying number of inserted cytosines in different mitochondrial molecules.Conclusion: This family establishes the nucleotide 961 thymidine deletion associated with a varying number of inserted cytosines in the mitochondrial 12S ribosomal RNA gene as the second pathogenic mutation that can predispose to aminoglycoside ototoxicity. It demonstrates the clinical relevance of taking a family history before administering aminoglycosides to any patient. In addition, it would be desirable for sporadic patients with aminoglycoside-induced hearing loss to be screened with molecular tests for the presence of the 1555 and 961 mutations. Such screening could significantly decrease the prevalence of aminoglycoside-induced hearing loss. Copyright (C) 1999 by W.B. Saunders Company.