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


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.


Available from: Silvia Giliani
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    • "The yeast las17-41 allele encodes a W41R mutation that is homologous to the W64R mutation in the WH1 domain of WASP (Fig EV1). This mutation causes classic WAS symptoms (Fillat et al, 2000; Jin et al, 2004). The growth of a yeast strain carrying this allele is completely impaired at 37°C and above, while it is normal at 22°C (Fig EV2). "
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    ABSTRACT: Since deleterious mutations may be rescued by secondary mutations during evolution, compensatory evolution could identify genetic solutions leading to therapeutic targets. Here, we tested this hypothesis and examined whether these solutions would be universal or would need to be adapted to one's genetic and environmental makeups. We performed experimental evolutionary rescue in a yeast disease model for the Wiskott–Aldrich syndrome in two genetic backgrounds and carbon sources. We found that multiple aspects of the evolutionary rescue outcome depend on the genotype, the environment, or a combination thereof. Specifically, the compensatory mutation rate and type, the molecular rescue mechanism, the genetic target, and the associated fitness cost varied across contexts. The course of compensatory evolution is therefore highly contingent on the initial conditions in which the deleterious mutation occurs. In addition, these results reveal biologically favored therapeutic targets for the Wiskott–Aldrich syndrome, including the target of an unrelated clinically approved drug. Our results experimentally illustrate the importance of epistasis and environmental evolutionary constraints that shape the adaptive landscape and evolutionary rate of molecular networks.
    Molecular Systems Biology 10/2015; 11(10). DOI:10.15252/msb.20156444 · 10.87 Impact Factor
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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
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