Hutchin T, Haworth I, Higashi K, Fischel-Ghodsian N, Stoneking M, Saha N, Arnos C, Cortopassi G
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033.
Nucleic Acids Res. 1993 Sep 11;21(18):4174-9. doi: 10.1093/nar/21.18.4174.
We have investigated the distribution of mitochondrial DNA polymorphisms in a rare maternally transmitted genetic trait that causes hypersensitivity to aminoglycoside antibiotics, in the hope that a characterization of its molecular basis might provide a molecular and cellular understanding of aminoglycoside-induced deafness (AGD). Here we report that the frequency of a particular mitochondrial DNA polymorphism, 1555G, is associated nonrandomly with aminoglycoside-induced deafness in two Japanese pedigrees, bringing the frequency of this polymorphism to 5 occurrences in 5 pedigrees of AGD, and in 4 of 78 sporadic cases in which deafness was thought to be the result of aminoglycoside exposure; both frequencies are significantly different from the occurrence of this mutation in the hearing population, which was 0 in 414 individuals surveyed. The 1555G polymorphism occurred in none of 34 aminoglycoside-resistant individuals. We propose a specific molecular mechanism for aminoglycoside hypersensitivity in individuals carrying the 1555G polymorphism, based on the three-dimensional structure of the ribosome, in which the 1555G polymorphism favors aminoglycoside binding sterically, by increasing access to the the ribosome cleft.
我们研究了一种罕见的母系遗传性状中线粒体DNA多态性的分布情况，该性状会导致对氨基糖苷类抗生素过敏，希望对其分子基础的表征能够提供对氨基糖苷类抗生素致聋（AGD）的分子和细胞层面的理解。在此我们报告，在两个日本家系中，一种特定的线粒体DNA多态性，即1555G，与氨基糖苷类抗生素致聋呈非随机关联，使得该多态性在5个AGD家系中的出现频率为5次，在78例被认为是氨基糖苷类抗生素暴露导致耳聋的散发病例中有4例出现；这两个频率与听力正常人群中该突变的发生率显著不同，在414名被调查个体中发生率为0。在34名对氨基糖苷类抗生素耐药的个体中均未出现1555G多态性。基于核糖体的三维结构，我们提出了携带1555G多态性个体对氨基糖苷类抗生素过敏的一种特定分子机制，其中1555G多态性通过增加对核糖体裂隙的可及性，在空间上有利于氨基糖苷类抗生素的结合。
