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Multidisciplinary approach to understanding the pathophysiology of the wiskott-aldrich syndrome towards improved healthcare.

Deliverables

The WASPNEST project had two main findings: - Activated WASp induces cell apoptosis: New mutations have been identified in the WAS gene that induce congenital neutropenia. This is associated with unregulated activation of WASp, which by unknown mechanisms induces premature cell cycle arrest and apoptosis. This result has the following implications: -- WASp may be toxic when unregulated and possibly when overexpressed. -- Unregulated activation of the cytoskeleton may promote cell death in other disease conditions. -- Elucidation of mechanisms to suppress activation of WASp may be therapeutically useful. --Gene therapy of WAS will probably require careful regulation of gene expression. - WASp participates in regulation of NK cell cytolytic activity: Mutations of the WASP gene that cause classical Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT) affect Natural Killer (NK) cells cytolytic activity, by impairing ability of Nk cells to form conjugates with cytotoxic target cells. The WASp protein directly participates in NK cell activation, as shown by the fact that crosslinking of CD16 or beta-2 integrins on the surface of NK cells results in rapid tyrosine phosphorylation of WASp and activation of cdc42. These results may explain the unique susceptibility of WAS patients to Herpesvirus infections. Furthermore, these abnormalities may be reversed in vitro by addition of exogenous IL-2. In addition, through the analysis of a large number of families with WAS/XLT, a genotype-phenotype correlation seems to exist, that may allow prediction of the clinical and immunological phenotype based on WASP gene mutation analysis and WASp protein expression. An extremely mild phenotype (intermittent X-linked thrombocytopenia), due to specific WASP gene mutations, has been identified during this project.