Zeiher B G, Eichwald E, Zabner J, Smith J J, Puga A P, McCray P B, Capecchi M R, Welsh M J, Thomas K R
Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
J Clin Invest. 1995 Oct;96(4):2051-64. doi: 10.1172/JCI118253.
The most common cause of cystic fibrosis is a mutation that deletes phenylalanine 508 in cystic fibrosis transmembrane conductance regulator (CFTR). The delta F508 protein is misprocessed and degraded rather than traveling to the apical membrane. We used a novel strategy to introduce the delta F508 mutation into the mouse CFTR gene. Affected epithelia from homozygous delta F508 mice lacked CFTR in the apical membrane and were Cl-impermeable. These abnormalities are the same as those observed in patients with delta F508 and suggest that these mice have the same cellular defect. 40% of homozygous delta F508 animals survived into adulthood and displayed several abnormalities found in human disease and in CFTR null mice. These animals should provide an excellent model to investigate pathogenesis and to examine therapies directed at correcting the delta F508 defect.
囊性纤维化最常见的病因是一种突变，该突变导致囊性纤维化跨膜传导调节因子（CFTR）中第508位苯丙氨酸缺失。ΔF508蛋白加工错误并被降解，而不是转运至顶端膜。我们采用了一种新策略，将ΔF508突变引入小鼠CFTR基因。纯合ΔF508小鼠的受影响上皮细胞顶端膜缺乏CFTR，且对氯离子不通透。这些异常与ΔF508患者中观察到的异常相同，表明这些小鼠存在相同的细胞缺陷。40%的纯合ΔF508动物存活至成年，并表现出人类疾病和CFTR基因敲除小鼠中发现的几种异常。这些动物应能为研究发病机制以及检验针对纠正ΔF508缺陷的治疗方法提供极佳的模型。
