Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene
Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene
复制标题
通过靶向破坏小鼠葡萄糖脑苷脂酶基因而建立的戈谢病动物模型
作者：
V. Tybulewicz;M. Tremblay;LaMarca;R. Willemsen;B. Stubblefield;S. Winfield;B. Zabłocka;E. Sidransky;B. Martin;S. Huang;K. A. Mintzer;H. Westphal;R. Mulligan;E. Ginns
高歇氏病是人类最常见的溶酶体贮积症，由常染色体遗传性葡萄糖脑苷脂酶（β-D-葡萄糖基-N-酰基鞘氨醇葡萄糖水解酶）1-6 缺陷所致，该酶负责降解鞘脂葡萄糖脑苷脂。戈谢病的动物模型对于研究其表型多样性和发病机制以及评估治疗方法非常重要。一种自然发生的犬类模型已被报道但尚未传播7。通过抑制葡萄糖脑苷脂酶来模拟动物疾病的尝试尚不充分8。在这里，我们通过基因靶向在胚胎干细胞中创建无效等位基因，并使用这些转基因细胞建立携带突变的小鼠品系，从而生成戈谢病动物模型9,10。这种突变的纯合小鼠的葡萄糖脑苷脂酶活性低于正常的 4%，在出生后 24 小时内死亡，并将葡萄糖脑苷脂储存在网状内皮系统细胞的溶酶体中。
GAUCHER'S disease is the most prevalent lysosomal storage disorder in humans and results from an autosomally inherited deficiency of the enzyme glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase)1–6, which is responsible for degrading the sphingolipid glucocerebroside. An animal model for Gaucher's disease would be important for investigating its phenorypic diversity and pathogenesis and for evaluating therapeutic approaches. A naturally occurring canine model has been reported but not propagated7. Attempts to mimic the disease in animals by inhibiting glucocerebrosidase have been inadequate8. Here we generate an animal model for Gaucher's disease by creating a null allele in embryonic stem cells through gene targeting and using these genetically modified cells to establish a mouse strain carrying the mutation9,10. Mice homozygous for this mutation have <4% of normal glucocerebrosidase activity, die within twenty-four hours of birth and store glucocerebroside in lysosomes of cells of the reticuloendothelial system.