Toivonen J M, O'Dell K M, Petit N, Irvine S C, Knight G K, Lehtonen M, Longmuir M, Luoto K, Touraille S, Wang Z, Alziari S, Shah Z H, Jacobs H T
Institute of Medical Technology & Tampere University Hospital, FIN-33014 University of Tampere, Finland.
Genetics. 2001 Sep;159(1):241-54. doi: 10.1093/genetics/159.1.241.
Mutations in mtDNA-encoded components of the mitochondrial translational apparatus are associated with diverse pathological states in humans, notably sensorineural deafness. To develop animal models of such disorders, we have manipulated the nuclear gene for mitochondrial ribosomal protein S12 in Drosophila (technical knockout, tko). The prototypic mutant tko(25t) exhibits developmental delay, bang sensitivity, impaired male courtship, and defective response to sound. On the basis of a transgenic reversion test, these phenotypes are attributable to a single substitution (L85H) at a conserved residue of the tko protein. The mutant is hypersensitive to doxycyclin, an antibiotic that selectively inhibits mitochondrial protein synthesis, and mutant larvae have greatly diminished activities of mitochondrial redox enzymes and decreased levels of mitochondrial small-subunit rRNA. A second mutation in the tko gene, Q116K, which is predicted to impair the accuracy of mitochondrial translation, results in the completely different phenotype of recessive female sterility, based on three independent transgenic insertions. We infer that the tko(25t) mutant provides a model of mitochondrial hearing impairment resulting from a quantitative deficiency of mitochondrial translational capacity.
线粒体翻译装置中由线粒体DNA编码的组分发生突变与人类多种病理状态相关，尤其是感音神经性耳聋。为了建立此类疾病的动物模型，我们对果蝇中线粒体核糖体蛋白S12的核基因进行了操控（技术敲除，tko）。典型的突变体tko(25t)表现出发育延迟、对惊吓敏感、雄性求偶行为受损以及对声音的反应缺陷。基于转基因回复试验，这些表型归因于tko蛋白保守残基处的单个替换（L85H）。该突变体对强力霉素高度敏感，强力霉素是一种选择性抑制线粒体蛋白合成的抗生素，突变幼虫的线粒体氧化还原酶活性大幅降低，线粒体小亚基rRNA水平也降低。基于三个独立的转基因插入，tko基因中的第二个突变Q116K预计会损害线粒体翻译的准确性，导致完全不同的隐性雌性不育表型。我们推断tko(25t)突变体提供了一个因线粒体翻译能力定量缺陷而导致线粒体听力障碍的模型。
