Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): Hotspots, effect on transcription, and translation and phenotype/genotype correlation

Department of Pediatrics, University of Washington, Seattle, WA 98109, USA.
Blood (Impact Factor: 10.45). 01/2005; 104(13):4010-9. DOI: 10.1182/blood-2003-05-1592
Source: PubMed

ABSTRACT The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype.

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    • "Unexpectedly, the WH1 domain and not the SH3 adaptor-binding proline-rich region of N-WASP was recruited to the virus (Moreau et al., 2000). This result was striking, as the majority of mutations leading to Wiskott-Aldrich syndrome are found in the WH1 domain of WASP (Jin et al., 2004). This observation led to the realization that vaccinia also recruits WIP, which interacts with the WH1 domain of WASP and Nck (Antó n et al., 1998; Moreau et al., 2000; Ramesh et al., 1997; Zettl and Way, 2002) (Figure 4). "
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    ABSTRACT: Intracellular pathogens have developed elaborate mechanisms to exploit the different cellular systems of their unwilling hosts to facilitate their entry, replication, and survival. In particular, a diverse range of bacteria and viruses have evolved unique strategies to harness the power of Arp2/3-mediated actin polymerization to enhance their cell-to-cell spread. In this review, we discuss how studying these pathogens has revolutionized our molecular understanding of Arp2/3-dependent actin assembly and revealed key signaling pathways regulating actin assembly in cells. Future analyses of microbe-host interactions are likely to continue uncovering new mechanisms regulating actin assembly and dynamics, as well as unexpected cellular functions for actin. Further, studies with known and newly emerging pathogens will also undoubtedly continue to enhance our understanding of the role of the actin cytoskeleton during pathogenesis and potentially highlight future therapeutic approaches.
    Cell host & microbe 09/2013; 14(3):242-55. DOI:10.1016/j.chom.2013.08.011 · 12.33 Impact Factor
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    • "Classic WAS that presents with the clinical triad is most often seen when mutations in the WASP gene lead to an absent or truncated form of the protein. If the WAS protein is normal in size despite the underlying mutation, it more frequently results in other phenotypes, including X-linked thrombocytopenia without immunodeficiency or X-linked neutropenia [Villa et al. 1995; Jin et al. 2004]. "
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    ABSTRACT: While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.
    08/2013; 4(4):270-90. DOI:10.1177/2040620713498161
    • "Several studies indicate a correlation between the clinical phenotype of WAS and the nature of the inherited mutation (Jin et al., 2004), with truncated or abolished WASp expression coinciding with the most severe cases (Ochs and Thrasher, 2006). In contrast, X-linked Neutropenia (XLN) in patients, results from constitutively active mutations in WASp, and presents with congenital neutropenia (Ancliff et al., 2006; Devriendt et al., 2001). "
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    ABSTRACT: Wiskott Aldrich syndrome (WAS) and X-linked neutropenia (XLN) are immunodeficiencies in which the functions of several haematopoietic cell lineages are perturbed due to mutations in the actin regulator WASp. From in vitro cell biology experiments and biochemical and structural approaches we know much about the functional domains of WASp, and how WASp might regulate the dynamic actin cytoskeleton downstream of activators such as Cdc42, but in vivo experiments are much more challenging. In patients there is a correlation between clinical disease and genotype, with severe reductions in WASp expression or function associating with complex multilineage immunodeficiency, whereas, specific mutations that cause constitutive activation of WASp result in congenital neutropenia. Here we take advantage of the genetic tractability and translucency of zebrafish larvae to first characterise how a null mutant in zfWASp influences the behaviour of neutrophils and macrophages in response to tissue damage and to clearance of infections. We then use this mutant background to study how leukocyte lineage-specific transgenic replacement with human WASp variants, (including normal wild type, and point mutations that either fail to bind Cdc42 or cannot be phosphorylated, and a constitutively active mutant equivalent to that seen in XLN patients), alter the capacity for generation of neutrophils, and their chemotactic response to wounds, and the phagocytic clearance capacity of macrophages. This model provides a unique insight into WASp-related immunodeficiency at both a cellular and whole organism level.
    Journal of Cell Science 07/2013; 126(18). DOI:10.1242/jcs.128728 · 5.43 Impact Factor
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