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 complex. 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 thrombocytopenia (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene. 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.

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

“…In presence of genital-cardiac malformations the lesion of G6PC3 gene has to be considered [53]. Activating mutations in the WAS gene have been found to be responsible for some cases of X-linked-SNC [54,55] (EO, IV, V, 8.1, B). Finally as patients with digenic mutations have been found [56], mutation search in a second gene known to be involved in SCN should also be considered.…”

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes

“…Three novel mutations (L270P, S272P, and I294T) clustered within the GTPase binding domain of WASP were recently identified in patients with a severe congenital form of X-linked neutropenia (XLN; Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009). The L270P, S272P, and I294T mutations destroy the autoinhibited conformation of WASP and generate an unfolded protein with enhanced actinpolymerizing activity (Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009).…”

“…Severe congenital neutropenia is caused by loss-of-function mutations in a variety of proteins including the genes encoding neutrophil elastase, HAX1, and the recently identified glucose-6-phosphatase catalytic subunit 3 (Ancliff, 2003;Klein et al, 2007;Boztug et al, 2009). The XLN-WASP mutations (L270P, S272P, and I294T) add to the genetic complexity of the disease (Devriendt et al, 2001;Ancliff et al, 2006;Beel et al, 2009). Although deficiency in neutrophil elastase, HAX1, and glucose-6-phosphatase catalytic subunit 3 can be explained by increased apoptosis of neutrophils and their precursors, it is difficult to predict how constitutively active WASP may induce neutropenia and how the function of other hematopoietic cells are affected.…”

A novel Wiskott-Aldrich syndrome protein (WASP) complex mutation identified in a WAS patient results in an aberrant product at the C-terminus from two transcripts with unusual polyA signals

“…Mutations in the Wiskott-Aldrich syndrome protein (WASP) gene, leading to a loss of function, have been described in patients with WAS and X-linked thrombocytopenia (XLT) (Derry et al 1994;Zhu et al 1995;Ochs and Rosen 1999). Gain of function mutations in the same gene have been found to cause X-linked severe congenital neutropenia (Devriendt et al 2001). The WASP gene has 12 exons and encodes for a cytoplasmatic protein (WASP), predominantly expressed in hematopoietic cells, and it plays a key role in regulating changes in cytoskeletal structure in response to external stimuli and signal transduction processes (Brickell et al 1998;Snapper and Rosen 1999).…”