Point mutations at the purine nucleoside phosphorylase locus impair thymocyte differentiation in the mouse.

Three point mutations on the Np(b) allele of the purine nucleoside phosphorylase locus in the mouse have been recovered by male germ cell mutagenesis. The mutants were backcrossed, 12-14 generations, and are designated in increasing order of severity of enzyme deficiency and phenotype: B6-NPE, Met-87 --> Lys; B6-NPF, Ala-228 --> Thr; and B6-NPG, Trp-16 --> Arg. A marked decline in total cell numbers per thymus occurs between 2 and 3 months for the more severe B6-NPF and B6-NPG mutants (35% and 52%, respectively) and by 8 months for the less severe B6-NPE mutation. The thymocyte population is thereafter characterized by a 3- or 8-fold expanded precursor, CD4-CD8- double-negative population and 15% or 55% reduced CD4+CD8+ double-positive cells for the B6-NPF and B6-NPG strains, respectively. Spleen lymphocyte Thy-1+ cells are reduced by 50% and spleen lymphocyte response to T cell mitogen and interleukin 2 is reduced by 80%. Increases of thymocyte dGTP pools of 5- and 2.5-fold for B6-NPF and B6-NPG mutants, respectively, are observed. The purine nucleoside phosphorylase-deficient mouse exhibits age-dependent progressive perturbations in thymocyte differentiation, reduced numbers of thymocytes, and reduced splenic T cell numbers and response. The progressive T cell deficit is similar to the human disorder.