title: Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70.
abstract: The protein tyrosine kinase, ZAP-70, is pivotally involved in transduction of Ag-binding signals from the TCR required for T cell activation and development. Defects in ZAP-70 result in SCID in humans and mice. We describe an infant with SCID due to a novel ZAP-70 mutation, comparable with that which arose spontaneously in an inbred mouse colony. The patient inherited a homozygous missense mutation within the highly conserved DLAARN motif in the ZAP-70 kinase domain. Although the mutation only modestly affected protein stability, catalytic function was absent. Despite identical changes in the amino acid sequence of ZAP-70, the peripheral T cell phenotypes of our patient and affected mice are distinct. ZAP-70 deficiency in this patient, as in other humans, is characterized by abundant nonfunctional CD4(+) T cells and absent CD8(+) T cells. In contrast, ZAP-70-deficient mice lack both major T cell subsets. Although levels of the ZAP-70-related protein tyrosine kinase, Syk, may be sufficiently increased in human thymocytes to rescue CD4 development, survival of ZAP-70-deficient T cells in the periphery does not appear to be dependent on persistent up-regulation of Syk expression.
authors: Department of Pediatrics, University of California, San Francisco, CA 94143, USA. elderm@peds.ucsf.edu
authors: M E
authors: ME
authors: Elder
authors: S
authors: S
authors: Skoda-Smith
authors: T A
authors: TA
authors: Kadlecek
authors: F
authors: F
authors: Wang
authors: J
authors: J
authors: Wu
authors: A
authors: A
authors: Weiss
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D001120:Arginine / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002384:Catalysis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D004792:Enzyme Precursors / Q000096:biosynthesis; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D001120:Arginine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D003545:Cysteine