Bindoff L A, Howell N, Poulton J, McCullough D A, Morten K J, Lightowlers R N, Turnbull D M, Weber K
Division of Clinical Neuroscience, Medical School, University of Newcastle upon Tyne, United Kingdom.
J Biol Chem. 1993 Sep 15;268(26):19559-64.
A patient with a mitochondrial myopathy and biochemically proven profound complex I deficiency has a new mutation in mtDNA. This A-to-G transition at position 3302, involving the aminoacyl stem of tRNA(Leu(UUR)), is associated with abnormal mitochondrial RNA processing. Northern analysis demonstrates marked accumulation of a polycistronic RNA precursor containing sequence for 16 S rRNA, tRNA(Leu(UUR)), and ND1. Comparison of skeletal muscle and skin fibroblasts suggests that the processing error may be quantitatively less severe in this tissue, and biochemical analysis shows that fibroblasts do not express a biochemical defect despite containing the mutation. Important qualitative differences in the processing of this RNA precursor were found when comparing muscle and skin fibroblasts. In muscle, processing appears to occur first at the 5'-end of the tRNA, generating 16 S rRNA plus a tRNA + ND1 intermediate. In fibroblasts, processing occurs at the 3'-end of the tRNA, generating a 16 S rRNA + tRNA intermediate. We suggest that the mutation at position 3302 induces abnormal mitochondrial RNA processing that is linked to the biochemical defect (profound loss of complex I activity), either by qualitative or quantitative abnormalities in the ND1 message. The restriction to skeletal muscle of both the processing error and the biochemical defect suggests that the observed tissue differences in RNA processing play a protective role in skin fibroblasts.
一名患有线粒体肌病且经生化证实存在严重复合体I缺陷的患者，其线粒体DNA（mtDNA）发生了新的突变。该突变位于3302位，由A到G的转换，涉及tRNA（Leu（UUR））的氨酰基茎，与线粒体RNA加工异常有关。Northern印迹分析显示，含有16S rRNA、tRNA（Leu（UUR））和ND1序列的多顺反子RNA前体明显积累。骨骼肌和皮肤成纤维细胞的比较表明，该组织中的加工错误在数量上可能不那么严重，并且生化分析表明，尽管成纤维细胞含有该突变，但并未表现出生化缺陷。在比较肌肉和皮肤成纤维细胞时，发现了这种RNA前体加工过程中重要的定性差异。在肌肉中，加工似乎首先发生在tRNA的5'端，产生16S rRNA加上一个tRNA + ND1中间体。在成纤维细胞中，加工发生在tRNA的3'端，产生一个16S rRNA + tRNA中间体。我们认为，3302位的突变诱导了异常的线粒体RNA加工，这与生化缺陷（复合体I活性严重丧失）有关，可能是通过ND1信息中的定性或定量异常。加工错误和生化缺陷都局限于骨骼肌，这表明观察到的RNA加工组织差异在皮肤成纤维细胞中起到了保护作用。
