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Cloning Regulatory Genes for Proliferation of Mitochondria and Effects on Mitochondrial Disease

克隆线粒体增殖调控基因及其对线粒体疾病的影响

基本信息

批准号：
01570141
负责人：
OHTA Shigeo
金额：
$ 1.41万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

The system coordinating expressions of nuclear coded mitochondrial proteins was investigated by examination of the 5'-flanking region of the human mitochondrial ATP synthase beta-subunit gene.At least two regions enhanced this promoter activity and at least one region repressed it. In one of the enhancing regions, a consensus sequence was found for the genes of other mitochondrial proteins such as those for cytochrome c1 and the pyruvate dehydrogenase alpha-subunit. This enhancing activity was independent of the orientation or location of the insert. Therefore, this is an enhancer that may be common to the nuclear genes of some mitochondrial proteins involved in energy transduction.MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a major heterogeneous mitochondrial diseases. For identifying a mutation in the mitochondrial gene, we isolated myogenic cell lines with distinctly different phenotypes from the same muscle tissue from a patient with MELAS : one was respiratory-deficient and the other was apparently normal.Only one A to G nucleotide transition at nucleotide number 3.243 in the tRNA-Leu (UUR) gene was found in whole mitochondrial DNA of the respiratory-deficient cells compared with that of the normal cells. This mutation was also found in 8 patients from unrelated families with MELAS in a heteroplasmic manner, but not in control individuals. Therefore, the single point mutation causes the functional abnormality in respiratory chain of mitochondria.

通过检测线粒体ATP合成酶β亚基基因的5‘侧翼区，研究了核编码线粒体蛋白的协调表达系统。至少有两个区域增强了这一启动子的活性，至少有一个区域抑制了它的活性。在其中一个增强区，发现了其他线粒体蛋白基因的共同序列，如细胞色素C1和丙酮酸脱氢酶α亚基的基因。这种增强活性与插入物的取向或位置无关。因此，这可能是一些参与能量传递的线粒体蛋白的核基因共有的增强子。MELAS(线粒体肌病、脑病、乳酸酸中毒和卒中样发作)是一种主要的异质性线粒体疾病。为了鉴定线粒体基因的突变，我们从一名MELAS患者的同一肌肉组织中分离出了表型明显不同的肌源性细胞株：一种是呼吸缺陷，另一种是明显正常的。与正常细胞相比，呼吸缺陷细胞的tRNA-Leu(UUR)基因中只有一种核苷酸从3.243位核苷酸转变为G核苷酸。在8例无血缘关系的MELAS家系患者中也发现了该突变，但在对照个体中未发现该突变。因此，单点突变导致线粒体呼吸链功能异常。