Ornithine deficiency in the arginase double knockout mouse
Ornithine deficiency in the arginase double knockout mouse
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DOI：
10.1016/j.ymgme.2006.04.007
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发表时间：
2006-09-01
影响因子：
3.8
通讯作者：
Grody, Wayne W.
中科院分区：
文献类型：
--
作者：
Deignan, Joshua L.;Livesay, Justin C.;Grody, Wayne W.
已经建立了基因敲除小鼠模型来研究精氨酸酶AI和AII缺乏的后果，包括单独和联合使用。At基因敲除动物在14日龄时死于高氨血症，而At基因敲除动物没有明显的表型。双重基因敲除(AI(-/-)/AII(-/-))表现出AI缺陷小鼠的表型，但额外的所有缺失并没有加剧观察到的AI基因敲除动物的表型。双基因敲除中的血浆氨基酸测量显示，与野生型相比，精氨酸水平增加了约100倍，鸟氨酸水平下降了约10倍。在精氨酸高度升高的双基因敲除中，肝脏鸟氨酸水平降至正常的2%。在双基因敲除小鼠的其他组织中，精氨酸和鸟氨酸也发生了变化，如肾脏、脑和小肠。这是第一次证明AI基因敲除小鼠的致命高氨血症几乎肯定是由于鸟氨酸缺乏所致，鸟氨酸是驱动尿素循环所需的氨基酸。其他研究表明，在AI缺陷动物死亡的同一年龄段，鸟氨酸转氨酶(OAT)在肠道中的表达迅速下降，这表明该酶对维持鸟氨酸的动态平衡至关重要，至少在小鼠发育的早期阶段是如此。虽然大多数人类AI缺陷患者出生时没有症状性高氨血症，但临床上可能已经存在显著的鸟氨酸缺乏症。(C)2006 Elsevier Inc.保留所有权利。
Knockout mouse models have been created to study the consequences of deficiencies in arginase AI and AII, both individually and combined. The At knockout animals die by 14 days of age from hyperammonemia, while the All knockout has no obvious phenotype. The double knockout (AI(-/-)/AII(-/-)) exhibits the phenotype of the AI-deficient mice, with the additional absence of All not exacerbating the observed phenotype of the AI knockout animals. Plasma amino acid measurements in the double knockout have shown arginine levels increased roughly 100-fold and ornithine decreased roughly 10-fold as compared to wildtype. Liver ornithine levels were reduced to 2% of normal in the double knockout with arginine very highly elevated. Arginine and ornithine were also altered in other tissues in the double knockout mice, such as kidney, brain, and small intestine. This is the first demonstration that the fatal hyperammonemia in the AI knockout mouse is almost certainly due to ornithine deficiency, the amino acid needed to drive the urea cycle. Others have shown that the expression of ornithine aminotransferase (OAT) rapidly decreases in the intestine at the same age when the AI-deficient animals die, indicating that this enzyme is critical to the maintenance of ornithine homeostasis, at least at this early stage of mouse development. Although most human AI-deficient patients have no symptomatic hyperammonemia at birth, it is possible that clinically significant ornithine deficiency is already present. (c) 2006 Elsevier Inc. All rights reserved.