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

312 Citations (Scopus)

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 - 2001

Fingerprint

Wiskott-Aldrich Syndrome
Mutation
Wiskott-Aldrich Syndrome Protein
rho GTP-Binding Proteins
GTP Phosphohydrolases
Mutant Proteins
Actin Cytoskeleton
Actins
Phenotype
Neutropenia, Severe Congenital, X-Linked
Genes
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van Den Oord, J. J., ... 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

Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. / Devriendt, Koenraad; Kim, Annette S.; Mathijs, Gert; Frints, Suzanna G M; Schwartz, Marianne; Van Den Oord, Joost J.; Verhoef, Gregor E G; Boogaerts, Marc A.; Fryns, Jean Pierre; You, Daoqi; Rosen, Michael K.; Vandenberghe, Peter.

In: Nature Genetics, Vol. 27, No. 3, 2001, p. 313-317.

Research output: Contribution to journalArticle

Devriendt, K, Kim, AS, Mathijs, G, Frints, SGM, Schwartz, M, Van Den Oord, JJ, Verhoef, GEG, Boogaerts, MA, Fryns, JP, You, D, Rosen, MK & Vandenberghe, P 2001, 'Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia', Nature Genetics, vol. 27, no. 3, pp. 313-317. https://doi.org/10.1038/85886
Devriendt K, Kim AS, Mathijs G, Frints SGM, Schwartz M, Van Den Oord JJ et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nature Genetics. 2001;27(3):313-317. https://doi.org/10.1038/85886
Devriendt, Koenraad ; Kim, Annette S. ; Mathijs, Gert ; Frints, Suzanna G M ; Schwartz, Marianne ; Van Den Oord, Joost J. ; Verhoef, Gregor E G ; Boogaerts, Marc A. ; Fryns, Jean Pierre ; You, Daoqi ; Rosen, Michael K. ; Vandenberghe, Peter. / Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. In: Nature Genetics. 2001 ; Vol. 27, No. 3. pp. 313-317.
@article{2920f5c7d28e416caa94ca13b9c5aac1,
title = "Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia",
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.",
author = "Koenraad Devriendt and Kim, {Annette S.} and Gert Mathijs and Frints, {Suzanna G M} and Marianne Schwartz and {Van Den Oord}, {Joost J.} and Verhoef, {Gregor E G} and Boogaerts, {Marc A.} and Fryns, {Jean Pierre} and Daoqi You and Rosen, {Michael K.} and Peter Vandenberghe",
year = "2001",
doi = "10.1038/85886",
language = "English (US)",
volume = "27",
pages = "313--317",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia

AU - Devriendt, Koenraad

AU - Kim, Annette S.

AU - Mathijs, Gert

AU - Frints, Suzanna G M

AU - Schwartz, Marianne

AU - Van Den Oord, Joost J.

AU - Verhoef, Gregor E G

AU - Boogaerts, Marc A.

AU - Fryns, Jean Pierre

AU - You, Daoqi

AU - Rosen, Michael K.

AU - Vandenberghe, Peter

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035093787&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035093787&partnerID=8YFLogxK

U2 - 10.1038/85886

DO - 10.1038/85886

M3 - Article

C2 - 11242115

AN - SCOPUS:0035093787

VL - 27

SP - 313

EP - 317

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -