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

Koenraad Devriendt, Annette S. Kim, Gert Mathijs, Suzanna G M Frints, Marianne Schwartz, Joost J. Van Den Oord, Gregor E G Verhoef, Marc A. Boogaerts, Jean Pierre Fryns, Daoqi You, Michael K. Rosen, Peter Vandenberghe

Research output: Contribution to journalArticle

319 Scopus citations

Abstract

The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex1. Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia2 (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene3-8. Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro, the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.

Original languageEnglish (US)
Pages (from-to)313-317
Number of pages5
JournalNature genetics
Volume27
Issue number3
DOIs
StatePublished - Mar 20 2001

ASJC Scopus subject areas

  • Genetics

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    Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van Den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J. P., You, D., Rosen, M. K., & Vandenberghe, P. (2001). Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nature genetics, 27(3), 313-317. https://doi.org/10.1038/85886