Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia

The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and it s homologs are important regulators of the actin cytoskeleton, mediating co mmunication between Rho-family GTPases and the actin nucleation/crosslinkin g factor. the Arp2/3 complex(1). Many WAS mutations impair cytoskeletal con trol in hematopoietic tissues, resulting in functional and developmental de fects that define the X-linked Wiskott-Aldrich syndrome (NAS) and the relat ed X-linked thrombocytopenia(2) (XLT), These diseases seem to result from r educed WASP signaling, often through decreased transcription or translation of the gene(3-8). Here we describe a new disease, X-linked severe congenit al neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD), In vitro. the mutant p rotein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibitio n is a key event in XLN. Our findings highlight the importance of precise r egulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellula r defects and clinical phenotypes.