Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver
arginase isoform,
arginase 1 (ARG1), which is the final step in the
urea cycle for detoxifying
ammonia.
ARG1 deficiency leads to
hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of
hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after
tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1
mRNA,
protein and liver
arginase activity, and exhibited symptoms of
hyperammonemia. Plasma
amino acid analysis revealed pronounced
hyperargininemia and significant alterations in
amino acid and guanidino compound metabolism, including increased
citrulline and
guanidinoacetic acid. Despite no alteration in
ornithine levels, concentrations of other
amino acids such as
proline and the
branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of
hyperargininemia. This model should prove useful for exploring potential treatment options of
ARG1 deficiency.