A Disease Mechanism Underlying Bleeding in Wiskott-Aldrich Syndrome

Abstract

The Wiskott-Aldrich Syndrome (WAS) is an × chromosome-linked immunodeficiency disorder. The most common symptom in WAS is bleeding. Several clinical investigations indicate that low platelet counts and defective platelet aggregation are the major causes of bleeding in WAS patients. However, the molecular bases underlying these defects are unclear. This study focuses on the molecular mechanism of defective platelet aggregation of WAS patients. The gene responsible for WAS encodes WAS protein (WASP). The mutations or deletion of WASP causes various functional defects in hematopoietic cells. We previously showed that binding of WASP to calcium- and integrin-binding protein (CIB) is required for activation of platelet integrin, αIIbβ3. I here demonstrate that blocking WASP binding to CIB reduces binding of talin to the β3 cytoplasmic tail, resulting in impaired activation of αIIbβ3. Impaired αIIbβ3 activation causes defective platelet aggregation, resulting in bleeding. This finding suggests a potential disease mechanism underlying bleeding seen in WAS patients.