Study on gene abnormality of mitochondrial encephalomyopathy and development of its transgenic mouse

我们发现三种线粒体DNA突变与MELAS相关（线粒体肌病、脑病、乳酸性酸中毒和卒中样发作）（Nature 1990; 348: 653 -3, Biochem Biophy Acta 1991; 1097: 338 -240, Biochem Biophys Res comm1994; 202: 1624-30）。这三个突变都位于同一个线粒体亮基转移RNA基因内，表明该基因与MELAS表型之间存在密切关系。由于其发病机制尚不清楚，因此有必要构建能够表达线粒体DNA的体外系统。3243突变存在于80%的MELAS患者中，已在母体传播糖尿病的家庭中得到确认（N Engl J Med 1994; 330: 962-8）。这可能显示出线粒体疾病的意外扩展。事实证明，线粒体基因疾病的基因型和表型之间的关系比核基因疾病更为复杂。由于无法将突变基因组引入生殖细胞的线粒体，我们无法开发出含有线粒体DNA突变的转基因小鼠。由于线粒体生物发生的基本机制还存在许多未知的问题，我们无法操作与核基因相同的系统。它需要一种新的方法来克服这个问题。

We have found three mitochondrial DNA mutations associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) (Nature 1990 ; 348 : 651-3, Biochim Biophy Acta 1991 ; 1097 : 238-240, Biochem Biophys Res Commun 1994 ; 202 : 1624-30). All the three mutations are located within the same mitochondrial leucyl transfer RNA gene, suggesting that there is a close relationship between the gene and MELAS phenotype. Because the mechanism of the pathogenesis remains to be clucidated, it is neceassary to construct an in vitro system that enables to express the mitochondrial DNA.The 3243 mutation, which1 is present in 80% of MELAS patients, has been recognized in families with maternally transmitted diabetes mellitus (N Engl J Med 1994 ; 330 : 962-8). This may show an unexpected expansion of mitochondrial disorders. It turns out that the relationship between genetype and phenotype in mitochondrial gene disorders is more complex than that in nuclear gene disorders.We could not develop a transgenic mouse harboring mitochondrial DNA mutation because of failure to introduce mutant genomes into mitochondria in germ cells. Since there were also many unkown matters relevant to basic mechanisms of mitochondrial biogenesis, we could not operate the same system used in nuclear gene. It needs a novel method that can overcome this problem.