Journal
JOURNAL OF IMMUNOLOGY
Volume 166, Issue 1, Pages 656-661Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.166.1.656
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Funding
- NCRR NIH HHS [M01 RR01271] Funding Source: Medline
- NIAMS NIH HHS [5 P60 AR20684] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR001271] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P60AR020684] Funding Source: NIH RePORTER
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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.
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