| abstract |
There is disclosed a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the conserved GTPase binding domain of the Wiskott-Aldrich syndrome protein (WASP). <I>In vitro</I>, the mutant protein is constitutively activated toward the Arp2/3 complex through disruption of an autoinhibitory domain in the wild type protein, suggesting that loss of WASP autoinhibition is a key event in XLN. These findings highlight the importance of precise regulation of WASP in hematopoietic development and function, since impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes. |