Genetic deficiency of purine nucleoside phosphorylase in the mouse. Characterization of partially and severely enzyme deficient mutants

Two independent mutations of purine nucleoside phosphorylase were identified in the first-generation progeny of male mice that had been treated with the mutagen N-ethylnitrosourea and mated to untreated females. The common allele in inbred strains is Np-1a and the mutants are assigned the gene symbols Np-1e and Np-1f. Heterozygotes had approximately half normal purine nucleoside phosphorylase activity in erythrocytes and activity of homozygotes was 17 and 5% of NP-1A for NP-1E and NP-1F, respectively. The following properties are consistent with both Np-1e and Np-1f being point mutations: the expression of residual but markedly reduced activity with normal Michaelis constants for inosine and phosphate, altered isoelectric points, and increased thermal lability. The reduction in erythrocyte activity was also evident in other tissues. A metabolic consequence of the mutations was increased purine nucleoside excretion. Inosine and guanosine, total 150 +/- 84 microM, and inosine, deoxyinosine, guanosine, and deoxyguanosine, total 1490 +/- 190 microM, were present in urine of Np-1e/Np-1e and Np-1f/Np-1f mice, respectively, but not in normal urine, less than 10 microM.