Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia Journal Article
| Authors: | 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. |
| Article 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. |
| Keywords: | signal transduction; adult; controlled study; gene mutation; human cell; major clinical study; neutropenia; protein conformation; proteins; phenotype; actin; thrombocytopenia; pedigree; dna; regulatory mechanism; x chromosome; base sequence; models, molecular; gene inactivation; dna primers; point mutation; cytoskeleton; linkage (genetics); genetic linkage; lymphocyte subsets; cross linking; wiskott aldrich syndrome protein; wiskott aldrich syndrome; wiskott-aldrich syndrome; wiskott-aldrich syndrome protein; humans; human; male; female; priority journal; article; vespidae; x chromosomal inheritance |
| Journal Title: | Nature Genetics |
| Volume: | 27 |
| Issue: | 3 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2001-03-01 |
| Start Page: | 313 |
| End Page: | 317 |
| Language: | English |
| DOI: | 10.1038/85886 |
| PUBMED: | 11242115 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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