Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation

Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders and increased incidence of malignancies. Classic WAS, and a milder form, X-linked thrombocytopenia, are caused by mutations of the WAS protein (WASP) gene. Recent investigations have provided evidence that WASP and several related proteins are involved in the reorganization of the actin cytoskeleton by activating Arp2/3-mediated actin polymerization. This function is controlled by the small GTPase Cdc42, which regulates the autoinhibitory loop formation of WASP. In addition, WASP is involved in cytoplasmic signaling via its interaction with a variety of adaptor molecules. Mutation analysis of large cohorts of WAS/X-linked thrombocytopenia patients has provided evidence for a strong correlation between phenotype and genotype.