PRODUCTION OF MYOPHATIC MODEL MICE WITH GENETIC CAVEOLIN-3 DEFICIENCY AND PHATHOLOGICAL ANALYSIS OF THEIR MUSCLES

小窝蛋白-3是整合在小窝中的肌肉特异性蛋白，小窝是质膜的小内陷。据报道，位于3 p25的小窝蛋白-3基因的突变涉及具有轻度临床症状的肢带型肌营养不良症（LGMDIC或小窝蛋白病）的发病机制，其通过常染色体显性遗传形式遗传。为了阐明其发病机制，我们开发了小窝蛋白-3缺陷小鼠作为小窝蛋白病的动物模型。Caveolin-3 mRNA及其蛋白在纯合突变小鼠中缺失。在杂合子突变小鼠中，mRNA及其蛋白质的大小都是正常的，但它们的数量减少了大约一半。骨骼肌细胞膜小窝的密度与小窝蛋白-3的含量大致成正比。在纯合子突变小鼠中，在8周龄的比目鱼肌和8周龄至30周龄的膈肌中识别出肌肉变性，尽管野生型和突变小鼠之间的生长和运动没有差异。在杂合突变小鼠中没有观察到明显的肌肉变性，表明由小窝蛋白-3基因破坏引起的病理变化通过隐性形式的遗传传递遗传。

Caveolin-3 is a muscle-specific protein integrated in the caveolae, which are small invaginations of the plasma membrane. Mutations of the caveolin-3 gene, localized at 3p25, have been reported to be involved in the pathogenesis of limb-girdle muscular dystrophy(LGMDIC or caveolinopathy) with mild clinical symptoms, inherited through autosomal dominant form of genetic transmission. To elucidate the pathogetic mechanism, we developed caveolin-3-deficient mice for use as animal models of caveolinopathy. Caveolin-3 mRNA and its protein were absent in homozygous mutant mice. In heterozygous mutant mice, both the mRNA and its protein were normal in size, but their amounts reduced by about half. The density of caveolae in skeletal muscle plasma membrane was roughly proportional to the amount of caveolin-3. In homozygous mutant mice, muscle degeneration was recognized in soleus muscles at 8 weeks of age and in the diaphragm from 8 weeks to 30 weeks, although there was no difference in growth and movement between wild-type and mutant mice. No apparent muscle degeneration was observed in heterozygous mutant mice, indicating that pathological changes caused by caveolin-3 gene disruption were inherited through the recessive form of genetic transmission.