Animal Models of OTC Deficiency and Their Gene Therapy

In 1976 Demars(148) reported that a sparse fur mouse whose phenotype was due to an X-chromosomal defect was prone to develop bladder stones which on analysis turned out to be orotic acid. Because orotic aciduria occurs in human OTC deficiency, OTC activities of the livers of these sparse fur (spf) mice were assayed and it was found that they indeed had an OTC deficiency. The male spf mouse is smaller than its litter mates, has no fur and wrinkled skin at birth which persists from five to seven days and then disappears to a variable extent as the males develop some hair and grow somewhat less than normal. The OTC activity in this spf/Y mouse liver had an activity of 22% of the control Oak Ridge 22A or C57BL mouse liver enzyme at the usual pH optimum of 7.6 to 8(148)(Table 6–1). However, male spf mice showed an increasing OTC activity as the pH of the medium was increased, the curve being sigmoidal in shape and reaching a maximum of 200% of the controls at pH 10. The midpoint of the sigmoid curve was 8.8. The normal mouse liver has an activity 80% of the spf/Y maximum at pH 10. The ornithine concentrations at half maximal velocity (Km) were approximately 0.2 mM in the normal and 0.6 mM in the spf livers at pH 8(148). When the Km for carbamyl phosphate, leucine inhibition and heat stability were tested, normal and spf males were the same.