Moraes C T, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon E A
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Mol Cell Biol. 1991 Mar;11(3):1631-7. doi: 10.1128/mcb.11.3.1631-1637.1991.
We identified two patients with progressive external ophthalmoplegia, a mitochondrial disease, who harbored a population of partially deleted mitochondrial DNA (mtDNA) with unusual properties. These molecules were deleted from mtDNA positions 548 to 4,442 and encompassed not only rRNA sequences but the heavy-strand promoter region as well. A 13-bp direct repeat was found flanking the breakpoint precisely, with the repeat at positions 535 to 547 located within the binding site for mitochondrial transcription factor 1 (mtTF1). This is the second mtDNA deletion involving a 13-bp direct repeat reported but is at least 10 times less frequent in the patient population than the former one. In situ hybridization studies showed that transcripts under the control of the light-strand promoter were abundant in muscle fibers with abnormal proliferation of mitochondria, while transcripts directed by the heavy-strand promoter, whether of genes residing inside or outside the deleted region, were not. The efficient transcription from the light-strand promoter implies that the major heavy-and light-strand promoters, although physically close, are functionally independent, confirming previous in vitro studies.
我们鉴定出两名患有进行性眼外肌麻痹（一种线粒体疾病）的患者，他们体内存在一群具有异常特性的部分缺失线粒体DNA（mtDNA）。这些分子从mtDNA的548位缺失至4442位，不仅包含rRNA序列，还包括重链启动子区域。在断点两侧精确发现了一个13bp的直接重复序列，位于535至547位的重复序列在线粒体转录因子1（mtTF1）的结合位点内。这是报道的第二例涉及13bp直接重复序列的mtDNA缺失，但在患者群体中的发生频率至少比前一例低10倍。原位杂交研究表明，轻链启动子控制下的转录本在线粒体异常增殖的肌纤维中丰富，而重链启动子指导的转录本，无论基因位于缺失区域内还是外，都不丰富。轻链启动子的高效转录意味着主要的重链和轻链启动子虽然在物理上接近，但在功能上是独立的，这证实了先前的体外研究。
