Knockout mouse models have been created to study the consequences of deficiencies in
arginase AI and AII, both individually and combined. The AI knockout animals die by 14 days of age from
hyperammonemia, while the AII knockout has no obvious phenotype. The double knockout (AI(-/-)/AII(-/-)) exhibits the phenotype of the AI-deficient mice, with the additional absence of AII 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.