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.
Publication types
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Case Reports
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs / genetics
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Amino Acid Motifs / immunology
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Animals
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Arginine / genetics
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / pathology
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Catalysis
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Cells, Cultured
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Cysteine / genetics
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Enzyme Precursors / biosynthesis
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Humans
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Infant
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Intracellular Signaling Peptides and Proteins
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Lymphocyte Activation / genetics
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Male
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Mice
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Mutation, Missense*
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Phosphorylation
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Phosphotyrosine / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics*
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Protein-Tyrosine Kinases / metabolism
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Receptors, Antigen, T-Cell / physiology
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Severe Combined Immunodeficiency / genetics
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Severe Combined Immunodeficiency / immunology
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Severe Combined Immunodeficiency / pathology
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Syk Kinase
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T-Lymphocyte Subsets / enzymology*
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T-Lymphocyte Subsets / pathology*
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Up-Regulation / genetics
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Up-Regulation / immunology
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Enzyme Precursors
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Intracellular Signaling Peptides and Proteins
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Receptors, Antigen, T-Cell
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Phosphotyrosine
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Arginine
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Zap70 protein, mouse
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Cysteine