Division of Human Genetics, University Hospital Bern, Switzerland.
Mitochondrion. 2011 May;11(3):488-96. doi: 10.1016/j.mito.2011.01.005. Epub 2011 Feb 1.
We report a sporadic case of chronic progressive external ophthalmoplegia associated with ragged red fibers. The patient presented with enlarged mitochondria with deranged internal architecture and crystalline inclusions. Biochemical studies showed reduced activities of complex I, III and IV in skeletal muscle. Molecular genetic analysis of all mitochondrial tRNAs revealed a G to A transition at nt 4308; the G is a highly conserved nucleotide that participates in a GC base-pair in the T-stem of mammalian mitochondrial tRNA(Ile). The mutation was detected at a high level (approx. 50%) in muscle but not in blood. The mutation co-segregated with the phenotype, as the mutation was absent from blood and muscle in the patient's healthy mother. Functional characterization of the mutation revealed a six-fold reduced rate of tRNA(Ile) precursor 3' end maturation in vitro by tRNAse Z. Furthermore, the mutated tRNA(Ile) displays local structural differences from wild-type. These results suggest that structural perturbations reduce efficiency of tRNA(Ile) precursor 3' end processing and contribute to the molecular pathomechanism of this mutation.
我们报告了一例散发性慢性进行性眼外肌麻痹伴破碎红纤维。患者表现为线粒体增大，内部结构紊乱，有结晶内含物。生化研究显示骨骼肌中复合物 I、III 和 IV 的活性降低。所有线粒体 tRNA 的分子遗传学分析显示 nt4308 处发生 G 到 A 的转换；G 是一个高度保守的核苷酸，参与哺乳动物线粒体 tRNA（Ile）的 T 茎中的 GC 碱基对。该突变在肌肉中检测到高比例（约 50%），但在血液中未检测到。该突变与表型共分离，因为患者健康的母亲的血液和肌肉中均未检测到该突变。该突变的功能特征分析显示，tRNAse Z 体外 tRNA（Ile）前体 3'末端成熟的速率降低了六倍。此外，突变的 tRNA（Ile）显示出与野生型的局部结构差异。这些结果表明结构扰动降低了 tRNA（Ile）前体 3'末端加工的效率，并导致该突变的分子病理机制。
