Mice deficient in the urea-cycle enzyme, carbamoyl phosphate synthetase I, die during the early neonatal period from hyperammonemia
Mice deficient in the urea-cycle enzyme, carbamoyl phosphate synthetase I, die during the early neonatal period from hyperammonemia
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DOI：
10.1002/hep.510290112
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发表时间：
1999-01-01
期刊：
影响因子：
13.5
通讯作者：
Wakamiya, M
中科院分区：
文献类型：
--
作者：
Schofield, JP;Cox, TM;Wakamiya, M
在哺乳动物的氨基酸催化过程中释放的氨具有高度神经毒性，并通过肝脏内表达的尿素循环的五种酶解毒。每种尿素循环酶的先天性缺陷都发生在人类中。氨甲酰磷酸合成酶I（CPSase I; EC 6.3.4.16）位于内部线粒体基质内并催化尿素循环的初始限速步骤。除非治疗，完全缺乏CPSase I，一种罕见的常染色体隐性遗传病，导致新生儿死亡。幸存者通常智力迟钝，在并发疾病或其他分解代谢压力期间经常发生高氨血症危机。在生物化学上，CPSase I缺乏症的特征是血氨、谷氨酰胺和丙氨酸水平高，瓜氨酸和精氨酸水平低或不存在。作为开发针对肝细胞的基因治疗的第一步，我们通过基因靶向产生了CPSase I缺陷小鼠。具有CPSase I纯合破坏的小鼠（CPSase [-/-]小鼠）在出生后36小时内死亡，具有压倒性的高氨血症，并且没有显著的肝脏病理学。该动物是人CPSase I缺乏的良好模型。
Ammonia liberated during amino acid catabolism in mammals is highly neurotoxic and is detoxified by the five enzymes of the urea cycle that are expressed within the liver. Inborn errors of each of the urea cycle enzymes occur in humans. Carbamoyl phosphate synthetase I(CPSase I; EC 6.3.4.16) is located within the inner mitochondrial matrix and catalyzes the initial rate-limiting step of the urea cycle. Unless treated, complete deficiency of CPSase I, a rare autosomal recessive disease, causes death in newborn infants. Survivors are often mentally retarded and suffer frequent hyperammonemic crises during intercurrent illness or other catabolic stresses. Biochemically, CPSase I deficiency is characterized by high levels of blood ammonia, glutamine, and alanine, with low or absent citrulline and arginine levels. As a first step toward the development of gene therapy directed to the hepatocyte, we have generated a CPSase I-deficient mouse by gene targeting. Mice with homozygous disruption of CPSase I (CPSase [-/-] mice) die within 36 hours of birth with overwhelming hyperammonemia, and without significant liver pathology. This animal is a good model of human CPSase I deficiency.