title: Point mutations at the purine nucleoside phosphorylase locus impair thymocyte differentiation in the mouse.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Calgary, AB Canada.
authors.forename: F F
authors.initials: FF
authors.lastname: Snyder
authors.forename: J P
authors.initials: JP
authors.lastname: Jenuth
authors.forename: E R
authors.initials: ER
authors.lastname: Mably
authors.forename: R K
authors.initials: RK
authors.lastname: Mangat
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D003062:Codon; D003433:Crosses, Genetic; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D010641:Phenotype; D017354:Point Mutation; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency* / Q000235:genetics*; D013154:Spleen; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology
chemical_list: D003062:Codon; D003845:Deoxycytosine Nucleotides; D003848:Deoxyguanine Nucleotides; D009838:Oligodeoxyribonucleotides; C024107:2'-deoxycytidine 5'-triphosphate; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase