Casano R A, Johnson D F, Bykhovskaya Y, Torricelli F, Bigozzi M, Fischel-Ghodsian N
Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, University of California, Los Angeles, School of Medicine, USA.
Am J Otolaryngol. 1999 May-Jun;20(3):151-6. doi: 10.1016/s0196-0709(99)90062-5.
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 familial 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.
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.
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.
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.
氨基糖苷类药物所致耳毒性在某些个体中似乎存在遗传易感性，线粒体12S核糖体RNA基因中的A1555G突变已被证明在所有家族性病例中是导致这种易感性的原因。一个有5名家庭成员在接触氨基糖苷类药物后失聪的意大利家庭前来就诊，分子分析排除了A1555G突变。本研究的目的是确定该家族中氨基糖苷类药物易感性的分子基础。
两名姐妹及其三个孩子在接触氨基糖苷类药物后出现了重度至极重度高频听力损失。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。还对核苷酸961周围的区域进行了克隆，并对单个克隆进行了测序。
12S核糖体RNA基因测序显示在961位有一个胸腺嘧啶缺失，该突变周围的序列模式复杂。对961突变周围的单个克隆进行测序表明，不同线粒体分子中插入胞嘧啶的数量各不相同。
这个家族确定了线粒体12S核糖体RNA基因中与不同数量插入胞嘧啶相关的961位胸腺嘧啶缺失是第二种可导致氨基糖苷类耳毒性的致病突变。它证明了在给任何患者使用氨基糖苷类药物之前询问家族史的临床相关性。此外，对于氨基糖苷类药物所致听力损失的散发性患者，进行分子检测以筛查1555和961突变的存在是可取的。这种筛查可以显著降低氨基糖苷类药物所致听力损失的发生率。
