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.

Congenital disease SNPs target lineage specific structural elements in protein kinases

“…For instance, in INSR, mutation of R1158 to tryptophan results in RabsonMendenhall syndrome (33), whereas mutation of the same arginine to glutamine results in Insulin resistance (34). Similarly, in ZAP70 mutation of R465 to histidine results in a selective T cell defect (35), whereas mutation of the same arginine to cysteine results in T-B-SCID (36). However, D166 mutations are characterized by a severe phenotype and lack of autophosphorylation activity (37,38), and substitutions of N171 by lysine results in severe diseases such as Robinow syndrome or Coffin-Lowry syndrome (23,39).…”

Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease

“…Phenotypic variation due to allelic heterogeneity has numerous precedents 12,13 . Alternatively, the variation in immune phenotype may reflect species-specific differences, as has been previously documented for the ZAP70 and ICOS genes 14,15 .…”

Tout ce que vous avez toujours voulu savoir sur la protéine ZAP-70

“…Le blocage complet de la différenciation B, chez les souris dont les gènes codant pour Syk et ZAP-70 ont été invalidés, démontre l'existence d'une redondance fonctionnelle entre ces deux protéines dans les lymphocytes B. Chez la souris, cette redondance fonctionnelle ne peut pas s'appliquer à la différenciation T, puisque les thymocytes murins n'expriment pas Syk [11]. En revanche, la sortie des lymphocytes T CD4 + humains en périphérie pourrait être due à la présence de Syk dans les thymocytes humains [30]. La perte d'expression de Syk dans les lymphocytes T CD4 + périphériques explique leur absence d'activité (Figure 2).…”