Frequency of mitochondrial 12S ribosomal RNA variants in an adult cystic fibrosis population
Frequency of mitochondrial 12S ribosomal RNA variants in an adult cystic fibrosis population
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DOI：
10.1097/fpc.0b013e328312b072
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发表时间：
2008-12-01
影响因子：
2.6
通讯作者：
Hardiman, Gary
中科院分区：
文献类型：
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作者：
Conrad, Douglas J.;Stenbit, Antine E.;Hardiman, Gary
在成人囊性纤维化患者群体中，革兰氏阴性菌，特别是铜绿假单胞菌，经常需要积极的治疗，包括全身抗生素、支气管扩张剂和呼吸道清除技术。氨基糖苷类药物包括妥布霉素经常用于控制这些慢性呼吸道感染。然而，它们会引起重要的肾毒性和耳毒性效应，从而显著改变生活质量。我们通过筛选线粒体12S核糖体RNA的变异，调查了典型的未筛查的北美囊性纤维化人群中氨基糖苷类耳毒性的遗传易感性，并注意到几个基因多态发生的频率高于预期，并与临床上有意义的听力损失病例相关。在被研究的人群中，两名具有1555A>；G转换的患者在服用无毒剂量的妥布霉素后都表现出严重的耳毒性。我们还在线粒体12S核糖体RNA中发现了新的同质遗传变异，其中一些发生在基因的高度保守区域，并存在于暴露于氨基糖苷类药物后的中度至重度耳毒性患者中。药物遗传学和基因组学18：1095-1102(C)2008 Wolters Kluwer Health|Lippincott Williams&Wilkins。
In adult cystic fibrosis patient populations, gram-negative bacteria, particularly Pseudomonas aeruginosa, frequently require aggressive therapy including systemic antibiotics, bronchodilators and airway clearance techniques. Aminoglycosides including tobramycin are used frequently to control these chronic airway infections. They, however, cause important nephrotoxic and ototoxic effects that can significantly alter the quality of life. We investigated the genetic predisposition to aminoglycoside ototoxicity in a typical unscreened North American cystic fibrosis population by screening for variants in mitochondrial 12S ribosomal RNA and noted several polymorphisms occurred at higher frequencies than expected and were associated with clinically significant cases of hearing loss. In the population studied, both patients possessing the 1555A>G transition exhibited profound ototoxicity after nontoxic dosing of tobramycin. We also identified new homoplasmic genetic variations in the mitochondrial 12S ribosomal RNA, several of which occurred in highly conserved regions of the gene and were present in patients with moderate-to-severe ototoxicity after exposure to aminoglycosides. Pharmacogenetics and Genomics 18:1095-1102 (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.