Ornithine Transcarbamylase Deficiency in Mutant Mice I. Studies on the Characterization of Enzyme Defect and Suitability as Animal Model of Human Disease

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Eighty-four young mice born from matings of four sparse-fur (spf)/+ females and two 22A +/Y males, were classified according to spf phenotype for males and orotic acid excretion and ornithine transcarbamylase (OTC) activity for females. The OTC activity of 15.2 ± 1.32 μmole citrulline/mg protein/hr shown by hemizygous affected males was 13% of that of normal males. Heterozygous females showed a much wider variation with a mean activity of 56% of normals.


Apparent Km and Vmax of the liver OTC in respect of carbamyl phosphate (CP) and ornithine (ORN) were measured for the hemizygous affected males, heterozygous females, and normal males and females. Km and Vmax (CP) for hemizygous affected males were significantly lower than normal males, normal females, and heterozygous females. Mean Km and Vmax (CP) values of heterozygous females were also significantly different from normal groups and hemizygous affected males. There were no significant differences for the values of Km (ORN) among various groups. However, the Vmax (ORN) of hemizygous males was significantly lower than the other three groups. Vmax (ORN) of the heterozygous females was also lower than the normal groups.


Mean value of 18.38 ± 5.13 μmole orotic acid/mg creatinine, excreted by spf/Y males, was significantly higher than all other groups. The average excretion of 7.38 ± 5.63 μmole by heterozygous females was also significantly higher than normal males (0.72 ± 0.23 μmole) and females (0.54 ± 0.27 μmole). The high orotic acid excretion by mutant mice underlines the basic similarity of these animals to the human counterpart.


There was no significant difference in the excretion of urinary urea between normal males and affected hemizygous males, or between normal females and heterozygous females.


Lower Km for carbamyl phosphate might be a characteristic of OTC from mutant mice with spf gene, which could be detected by urinary orotic acid measurement. These mice would prove to be useful animal models for studying nutritional and therapeutic measures to alleviate the consequences of OTC deficiency in children. Characterization of the defect of a mutant enzyme in an animal model should lead to greater understanding of the human disease counterpart. These studies would also be helpful in investigation of other inherited hyperammonemic syndromes.

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