Human
arginase deficiency is characterized by
hyperargininemia and infrequent episodes of
hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation,
seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by
weight loss at around day 15, and death occurs typically by postnatal day 17 with
hyperargininemia and markedly elevated
ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing
therapy for the more common presentation of
arginase deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of
arginase deficiency also resulted in lethality. Animal survival and
ammonia levels,
body weight, circulating
amino acids, and tissue
arginase levels were examined as outcome parameters after widespread
Cre-recombinase activation in a conditional knockout model of
arginase 1 deficiency. One hundred percent of adult female and 70% of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of
tamoxifen administration. Animals demonstrated elevated circulating
ammonia and
arginine at the onset of phenotypic abnormalities. In addition, brain and liver
amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of
arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile-onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene- and cell-based
therapies for this disorder that will not be limited by the small animal size of neonatal
therapy and for developing a better understanding of the characteristics of
hyperargininemia.