Weber K, Wilson J N, Taylor L, Brierley E, Johnson M A, Turnbull D M, Bindoff L A
Division of Neurology, The Medical School, Newcastle upon Tyne, United Kingdom.
Am J Hum Genet. 1997 Feb;60(2):373-80.
We have identified a new mutation in mtDNA, involving tRNALeu(CUN) in a patient manifesting an isolated skeletal myopathy. This heteroplasmic A-->G transition at position 12320 affects the T psi C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets, and skeletal muscle showed that only skeletal muscle contained the mutation and that only this tissue demonstrated a biochemical defect of respiratory-chain activity. In a series of four muscle-biopsy specimens taken over a 12-year period, there was a gradual increase, from 70% to 90%, in the overall level of mutation, as well as a marked clinical deterioration. Single-fiber PCR confirmed that the proportion of mutant mtDNA was highest in cytochrome c oxidase-negative fibers. This study, which reports a mutation involving tRNALeu(CUN), demonstrates clearly that mtDNA point mutations can accumulate over time and may be restricted in their tissue distribution. Furthermore, clinical deterioration seemed to follow the increase in the level of mutation, although, interestingly, the appearance of fibers deficient in respiratory-chain activity showed a lag period.
我们在一名表现为孤立性骨骼肌病的患者中发现了线粒体DNA（mtDNA）的一个新突变，该突变涉及亮氨酰tRNA（tRNALeu(CUN)）。这个位于12320位点的异质性A→G转换影响了保守位点的TψC环，在120名对照中未发现该突变。对培养的成纤维细胞、白细胞/血小板和骨骼肌的分析表明，只有骨骼肌含有该突变，并且只有这个组织表现出呼吸链活性的生化缺陷。在12年期间采集的一系列4份肌肉活检标本中，突变的总体水平从70%逐渐增加到90%，同时临床症状明显恶化。单纤维PCR证实，突变型mtDNA的比例在细胞色素c氧化酶阴性纤维中最高。这项报告涉及tRNALeu(CUN)突变的研究清楚地表明，mtDNA点突变可随时间积累，并且其组织分布可能具有局限性。此外，临床恶化似乎随着突变水平的增加而出现，不过有趣的是，呼吸链活性缺乏的纤维的出现存在滞后现象。
