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 phos phorylase locus in the mouse have been recovered by male germ cell mut agenesis. The mutants vc ere backcrossed, 12-14 generations, and are d esignated in increasing order of severity of enzyme deficiency and phe notype: B6-NPE, Met-87-->Lys; B6-NPF, Ala-228-->Thr; and B6-NPG, Trp-1 G-->Arg. A marked decline in total cell numbers per thymus occurs betw een 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 muta tion. 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 i nterleukin 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 observ ed, The purine nucleoside phosphorylase-deficient mouse exhibits age-d ependent progressive perturbations in thymocyte differentiation, reduc ed numbers of thymocytes, and reduced splenic T cell numbers and respo nse. The progressive T cell deficit is similar to the human disorder.