Mouse model for human arginase deficiency
Mouse model for human arginase deficiency
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DOI：
10.1128/mcb.22.13.4491-4498.2002
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发表时间：
2002-07-01
影响因子：
5.3
通讯作者：
Cederbaum, SD
中科院分区：
文献类型：
--
作者：
Iyer, RK;Yoo, PK;Cederbaum, SD
肝精氨酸酶 (AI) 缺乏会导致高精氨酸血症 (OMIM 207800)，这是一种以进行性精神障碍、生长迟缓和痉挛为特征的疾病，有时会出现致命的高氨血症发作。我们通过同源重组构建了携带无功能U基因的敲除小鼠品系。精氨酸酶 AI 敲除小鼠完全缺乏肝脏精氨酸酶 (AI) 活性，表现出严重的高氨血症症状，并在出生后 10 至 14 天之间死亡。在高氨血症危机期间，这些小鼠的血浆氨水平比正常动物增加 10 倍以上。 AI缺陷动物的肝脏表现出肝细胞异常，包括细胞肿胀和内含物。血浆氨基酸分析显示，敲除基因中的平均精氨酸水平大约是野生型的四倍，是杂合子的三倍；对于野生型或杂合子小鼠，精氨酸酶缺乏的生化后果是可以理解的，平均脯氨酸水平约为脯氨酸和鸟氨酸水平的三分之一，鸟氨酸水平分别为脯氨酸和鸟氨酸水平的一半。谷氨酸、瓜氨酸和组氨酸水平比表型正常动物高约 1.5 倍。支链氨基酸缬氨酸、异亮氨酸和亮氨酸的浓度是表型正常动物中浓度的 0.4 至 0.5 倍。总之，AI缺陷小鼠复制了人类状况的几个病理生物学方面，并且应该被证明是进一步研究疾病机制和探索治疗方案的有用模型，例如苯丁酸钠和/或鸟氨酸的药物给药以及基因治疗方案的开发。
Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional U gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.