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

Nature Genetics volume 27, pages 313–317 (2001)Cite this article

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 gene3,4,5,6,7,8. 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.

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Figure 1: L270P WASP mutation in XLN.
Figure 2: Ribbons30 depiction of the GBD4-C structure, showing sidechain of L270.
Figure 3: WASP L270P proteins are unfolded and constitutively active.

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Acknowledgements

We thank Y. Benoit, E. Baeten, F. Van Aelst and M. Holvoet for patient materials; R. Rohatgi and J. Peterson for discussions; D. Nelson for the anti-WASP antibody; and L. Notarangelo for the XLT cell line; and K. Vanstraelen and X. Bossuyt for help. K.D. and P.V. are Senior Clinical Investigators of the Fund for Scientific Research–Flanders (Belgium) (FWO-Vlaanderen). A.S.K. is supported by a fellowship from the Damon Runyon-Walter Winchell Foundation. M.K.R. acknowledges support from the National Institutes of Health (PECASE program), Arnold and Mabel Beckman Foundation and Sidney Kimmel Foundation for Cancer Research.

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Author notes

  1. Koenraad Devriendt and Annette S. Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium

    Koenraad Devriendt, Gert Mathijs, Suzanna G.M. Frints & Jean-Pierre Fryns

  2. Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Annette S. Kim, Daoqi You & Michael K. Rosen

  3. Department of Clinical Genetics, University Hospital, Rigshospitalet 4062, Copenhagen, Denmark

    Marianne Schwartz

  4. Department of Pathology, Laboratory of Histo- and Cytochemistry, University Hospital Leuven, Leuven, Belgium

    Joost J. Van den Oord

  5. Laboratory for Experimental Hematology, University of Leuven, Leuven, Belgium

    Gregor E.G. Verhoef, Marc A. Boogaerts & Peter Vandenberghe

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  1. Koenraad Devriendt
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Correspondence to Michael K. Rosen or Peter Vandenberghe.

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Devriendt, K., Kim, A., Mathijs, G. et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 27, 313–317 (2001). https://doi.org/10.1038/85886

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