Mice deficient in the urea-cycle enzyme, carbamoyl phosphate synthetase I,die during the early neonatal period from hyperammonemia

Ammonia liberated during amino acid catabolism in mammals is highly neuroto xic and is detoxified by the five enzymes of the urea cycle that are expres sed 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 loca ted within the inner mitochondrial matrix and catalyzes the initial rate-li miting step of the urea cycle. Unless treated, complete deficiency of CPSas e I, a rare autosomal recessive disease, causes death in newborn infants. S urvivors are often mentally retarded and suffer frequent hyperammonemic cri ses during intercurrent illness or other catabolic stresses. Biochemically, CPSase I deficiency is characterized by high levels of blood ammonia, glut amine, and alanine, with low or absent citrulline and arginine levels. As a first step toward the development of gene therapy directed to the hepatocy te, we have generated a CPSase I-deficient mouse by gene targeting. Mice wi th homozygous disruption of CPSase I (CPSase [-/-] mice) die within 36 hour s of birth with overwhelming hyperammonemia, and without significant liver pathology. This animal is a good model of human CPSase I deficiency.