Positional cloning of carnitine trasporter gene and its comtribution to the pathophysiological changes

肉毒碱转运蛋白基因的定位克隆及其对病理生理变化的贡献

基本信息

批准号：
08457267
负责人：
KUWAJIMA Masamichi
金额：
$ 3.01万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

The exact roles playd by carnitine in vivo have remained unclear. Our recent discovery of mice with systemic carnitine dificiency (JVS mice) offers the possibility of improvement of this circumstance. These JVS mice show symptoms such as fatty liver, hyperammonemia, hypoglycemia, cardiomegaly and skeletal muscle degeneration. We have been analyzin the histological, biochemical and molecular biological features of tissues from various sites of their bodies, focusing on the analysis of the relationship between carnitine deficiency and the diverse symptoms exhibited by these mice.We have obtained the following findings :1. As early as 2 weeks of age, JVS mice had higher absolute heart weights and higher retios of heart weight to body weight than controle mice. Hypertrophy of my ocardial cells was seen, and the nuclei of these cells tended to be larger in JVS mice. When observed under an electron microscope, the nuclei were slightly hypertrophic and not a few cells showed marked increase in mitochondria. The levels of carnitine palmitoyl transferase I (CPTI) mRNA and CPT II mRNA differted from those in controle mice.2. High-affinity carnitine transport activity was absent in the fibroblasts of JVS mice. This indicates that JVS mice can serve as an animal model of human primary carnitine dificiency.3. The symptoms seen in JVS mice are genetically transmitted in an autosomal recessive manner. It is thougt that a single gene is responsible for all these symptoms. The JVS gene was located on chromosome 11.

肉碱在体内发挥的确切作用仍不清楚。我们最近发现的全身性肉毒碱缺乏症小鼠（JVS小鼠）为改善这种情况提供了可能性。这些JVS小鼠表现出脂肪肝、高氨血症、低血糖、心脏扩大和骨骼肌变性等症状。我们对小鼠体内不同部位组织的组织学、生化和分子生物学特征进行了分析，重点分析了肉毒碱缺乏与这些小鼠表现出的各种症状之间的关系。我们得到了以下发现： 1．早在 2 周龄时，JVS 小鼠就比对照小鼠具有更高的绝对心脏重量和更高的心脏重量与体重的比率。我发现我的心室细胞肥大，并且 JVS 小鼠中这些细胞的细胞核往往更大。电镜下观察，细胞核轻度肥大，不少细胞线粒体明显增多。肉毒碱棕榈酰转移酶I（CPTI）mRNA和CPT II mRNA水平与对照小鼠存在差异。 2． JVS 小鼠的成纤维细胞中不存在高亲和力肉碱转运活性。这表明JVS小鼠可以作为人类原发性肉碱缺乏症的动物模型。 3． JVS 小鼠的症状以常染色体隐性方式遗传。据认为，所有这些症状都是由一个基因造成的。 JVS基因位于11号染色体上。