权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

线粒体脑肌病基因异常研究及其转基因小鼠的研制

基本信息

批准号：
05670583
负责人：
GOTO Yuichi
金额：
$ 1.28万
依托单位：
National Center of Neurology and Psychiatry
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

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.

我们已经发现了三种与MELAS相关的线粒体DNA突变（线粒体肌病、脑病、乳酸性酸中毒和中风样发作）（Nature 1990 ; 348：651-3，Biochim Biophy Acta 1991 ; 1097：238-240，Biochem Biophys Res Commun 1994 ; 202：1624-30）。这3个突变均位于同一线粒体亮氨酰转移RNA基因内，提示该基因与MELAS表型有密切关系。由于发病机制尚不清楚，因此有必要建立一个体外表达线粒体DNA的系统，在80%的MELAS患者中存在3243突变，这一点已在母系传播的糖尿病家族中得到确认（N Engl J Med 1994 ; 330：962-8）。这可能表明线粒体疾病的意外扩展。线粒体基因异常的基因型与表型之间的关系比核基因异常更为复杂，由于未能将突变基因组导入生殖细胞的线粒体，我们未能培育出携带线粒体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，我们不能像核基因那样操作。它需要一种新的方法来克服这个问题。