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

肉碱在体内扮演的确切角色尚不清楚。我们最近发现的全身性肉碱缺乏小鼠(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、心脏肥大和骨骼肌退化等症状。本文对JVS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，着重分析了肉碱缺乏与其表现出的各种症状的关系。结果表明：1.早在2周龄时，JVS小鼠的绝对心脏重量和心脏重量与体重的比值就高于对照组小鼠。我的心肌细胞肥大，在JVS小鼠中，这些细胞的核往往更大。在电子显微镜下观察，细胞核轻度肥大，不少细胞线粒体明显增多。结果：1.肉毒碱棕榈酰转移酶I(CPTI)和CPT II的mRNA表达水平与对照小鼠不同。JVS小鼠成纤维细胞缺乏高亲和力肉碱转运活性。这表明JVS小鼠可以作为人原发性肉碱缺乏的动物模型。在JVS小鼠中看到的症状是以常染色体隐性遗传的方式遗传的。人们认为，导致所有这些症状的是一个单一的基因。JVS基因位于11号染色体上。

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.