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

小窝蛋白-3是一种肌肉特异性蛋白，整合在小窝中，小窝是质膜上的小凹陷。小窝蛋白-3基因突变位于3p25，已被报道与肢体带状肌营养不良(LGMDIC或小窝病变)的发病机制有关，临床症状轻微，遗传方式为常染色体显性遗传。为了阐明其致病机制，我们建立了小窝蛋白-3缺陷小鼠作为小窝病变的动物模型。Caveolin-3mRNA及其蛋白在纯合子突变小鼠中缺失。在杂合突变小鼠中，mRNA及其蛋白的大小都是正常的，但它们的数量减少了大约一半。骨骼肌质膜上的小窝密度与小窝蛋白-3的含量大致成正比。在纯合子突变小鼠中，8周龄的比目鱼肌和8-30周的横隔肌出现肌肉变性，尽管野生型和突变小鼠的生长和运动没有差异。杂合突变小鼠未见明显的肌肉变性，表明小窝蛋白-3基因突变所致的病理改变是通过隐性遗传方式遗传的。

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.