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

• Published in: Nature genetics Vol. 27; no. 3; pp. 313 - 317
• Main Authors: Kim, Annette S, Schwartz, Marianne, Devriendt, Koenraad, Fryns, Jean-Pierre, Rosen, Michael K, Verhoef, Gregor E.G, Frints, Suzanna G.M, Van den Oord, Joost J, Vandenberghe, Peter, Mathijs, Gert, Boogaerts, Marc A, You, Daoqi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-03-2001
• Subjects: Base Sequence; Biological and medical sciences; Blood platelets; Complications and side effects; Congenital diseases; Diagnosis; DNA - genetics; DNA Primers - genetics; Female; Females; Gene mutations; Genetic aspects; Genetic Linkage; Hematologic and hematopoietic diseases; Humans; Lymphocyte Subsets; Male; Males; Medical sciences; Models, Molecular; Monoclonal antibodies; Mutation; Neutropenia; Neutropenia - blood; Neutropenia - congenital; Neutropenia - genetics; Neutrophils; Nucleation; Other diseases. Hematologic involvement in other diseases; Pedigree; Point Mutation; Protein Conformation; Proteins; Proteins - chemistry; Proteins - genetics; Publishing; Risk factors; WAS gene; Wiskott-Aldrich syndrome; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome Protein; X Chromosome - genetics; Belgium; New York; United States > US; Human; Sex linked character; Signal transduction; Leukopenia; Gene; Cytoskeleton; Homology; Hemopathy; Molecular complex; X-Chromosome; Mutation; Neutropenia
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/85886

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.