Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
PLoS Genet. 2012;8(6):e1002766. doi: 10.1371/journal.pgen.1002766. Epub 2012 Jun 21.
Mutations in the human Zip4 gene cause acrodermatitis enteropathica, a rare, pseudo-dominant, lethal genetic disorder. We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder. We found that the enterocyte Zip4 gene in mice is essential throughout life, and loss-of-function of this gene rapidly leads to wasting and death unless mice are nursed or provided excess dietary zinc. An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts. Labile zinc in Paneth cells was lost, followed by diminished Sox9 (sex determining region Y-box 9) and lysozyme expression, and accumulation of mucin, which is normally found in goblet cells. This was accompanied by dysplasia of the intestinal crypts and significantly diminished small intestine cell division, and attenuated mTOR1 activity in villus enterocytes, indicative of increased catabolic metabolism, and diminished protein synthesis. This was followed by disorganization of the absorptive epithelium. Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs whereas iron, manganese, and copper slowly accumulated to high levels in the liver as the disease progressed. These studies strongly suggest that wasting and lethality in acrodermatitis enteropathica patients reflects the loss-of-function of the intestine zinc transporter ZIP4, which leads to abnormal Paneth cell gene expression, disruption of the intestinal stem cell niche, and diminished function of the intestinal mucosa. These changes, in turn, cause a switch from anabolic to catabolic metabolism and altered homeostasis of several essential metals, which, if untreated by excess dietary zinc, leads to dramatic weight loss and death.
人类 Zip4 基因突变会导致肠病性肢端皮炎，这是一种罕见的、拟显性、致死性遗传性疾病。我们在小鼠中创建了一种可诱导的、肠细胞特异性的该基因敲除模型，该模型模拟了这种人类疾病。我们发现，小鼠肠细胞中的 Zip4 基因在整个生命周期中都是必需的，该基因的功能丧失会迅速导致消瘦和死亡，除非小鼠被哺乳或提供过量的膳食锌。敲除的一个初始效应是 Paneth 细胞的重编程，Paneth 细胞有助于隐窝中的肠干细胞龛。Paneth 细胞中的不稳定锌丢失，随后 Sox9（性别决定区 Y 框 9）和溶菌酶表达减少，粘蛋白积累，而粘蛋白通常存在于杯状细胞中。这伴随着肠隐窝的发育不良，小肠细胞分裂显著减少，绒毛肠细胞中的 mTOR1 活性减弱，表明代谢增加，蛋白质合成减少。随后吸收上皮组织紊乱。Zip4 敲除小鼠的小肠、肝脏和胰腺的元素分析表明，这些器官中的总锌急剧且迅速减少，而铁、锰和铜随着疾病的进展缓慢积累到高水平。这些研究强烈表明，肠病性肢端皮炎患者的消瘦和致死反映了肠道锌转运蛋白 ZIP4 的功能丧失，这导致了异常的 Paneth 细胞基因表达、肠干细胞龛的破坏以及肠黏膜功能的减弱。这些变化反过来又导致从合成代谢到分解代谢的转变，以及几种必需金属的体内平衡改变，如果不通过过量的膳食锌治疗，会导致体重明显减轻和死亡。
