Genomes and Genes
wiskott aldrich syndrome
Summary: A rare, X-linked immunodeficiency syndrome characterized by ECZEMA; LYMPHOPENIA; and, recurrent pyogenic infection. It is seen exclusively in young boys. Typically, IMMUNOGLOBULIN M levels are low and IMMUNOGLOBULIN A and IMMUNOGLOBULIN E levels are elevated. Lymphoreticular malignancies are common.
- Lutskiy M, Beardsley D, Rosen F, REMOLD O DONNELL E. Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome. Blood. 2005;106:2815-7 pubmed..The importance of reconstituting the NK-cell lineage is discussed. ..
- Snapper S, Rosen F. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol. 1999;17:905-29 pubmed..WASP/N-WASP may depolymerize actin directly and/or serve as an adaptor or scaffold for these signaling molecules in a complex cascade that regulates the cytoskeleton. ..
- Wada T, Schurman S, Garabedian E, Yachie A, Candotti F. Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome. Blood. 2005;106:3895-7 pubmed..These findings suggest that WASP deficiency does not limit thymic generation of a normal TCR and indicate that T-cell oligoclonality may contribute to the immunodeficiency in older patients with WAS. ..
- Derry J, Kerns J, Weinberg K, Ochs H, Volpini V, Estivill X, et al. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995;4:1127-35 pubmed..The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation. ..
- Gismondi A, Cifaldi L, Mazza C, Giliani S, Parolini S, Morrone S, et al. Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood. 2004;104:436-43 pubmed..We also found that WASp undergoes tyrosine phosphorylation upon CD16 or beta2-integrin engagement on NK cells. ..
- Kim M, Kim E, Kim D, Choi I, Moon T, Yoon C, et al. Two novel mutations of Wiskott-Aldrich syndrome: the molecular prediction of interaction between the mutated WASP L101P with WASP-interacting protein by molecular modeling. Biochim Biophys Acta. 2004;1690:134-40 pubmed..A possible model for the molecular pathogenesis of WAS has been proposed by analyzing the interactions of WASP and WIP using a molecular modeling study. ..
- Wada T, Schurman S, Otsu M, Garabedian E, Ochs H, Nelson D, et al. Somatic mosaicism in Wiskott--Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A. 2001;98:8697-702 pubmed
- Andreu N, Aran J, Fillat C. Novel membrane cell projection defects in Wiskott-Aldrich syndrome B cells. Int J Mol Med. 2007;20:445-50 pubmed..Such alterations most probably result from a WASP dysfunction, given that a retroviral gene transfer of a corrected form of the WASP gene was able to rescue the abnormal phenotypes. ..
- Badour K, Zhang J, Shi F, Leng Y, Collins M, Siminovitch K. Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation. J Exp Med. 2004;199:99-112 pubmed
- Knutsen A, Steffen M, Wassmer K, Wall D. Umbilical cord blood transplantation in Wiskott Aldrich syndrome. J Pediatr. 2003;142:519-23 pubmedTo report the use of umbilical cord blood (UCB) stem cell transplantation in Wiskott Aldrich syndrome (WAS) when a matched sibling donor was unavailable...
- Strom T, Gabbard W, Kelly P, Cunningham J, Nienhuis A. Functional correction of T cells derived from patients with the Wiskott-Aldrich syndrome (WAS) by transduction with an oncoretroviral vector encoding the WAS protein. Gene Ther. 2003;10:803-9 pubmed..The demonstration that correction of T cell defects can be achieved by gene transfer supports continued efforts to develop gene therapy for WAS. ..
- de Noronha S, Hardy S, Sinclair J, Blundell M, Strid J, Schulz O, et al. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood. 2005;105:1590-7 pubmed
- Martin F, Toscano M, Blundell M, Frecha C, Srivastava G, Santamaria M, et al. Lentiviral vectors transcriptionally targeted to hematopoietic cells by WASP gene proximal promoter sequences. Gene Ther. 2005;12:715-23 pubmed..Therefore, lentiviral vectors incorporating proximal promoter sequences from the WASP gene confer hematopoietic-specific, and physiological protein expression...
- Dupré L, Marangoni F, Scaramuzza S, Trifari S, Hernandez R, Aiuti A, et al. Efficacy of gene therapy for Wiskott-Aldrich syndrome using a WAS promoter/cDNA-containing lentiviral vector and nonlethal irradiation. Hum Gene Ther. 2006;17:303-13 pubmed..The efficacy of WAS gene transfer into HSCs, using the WAS promoter-containing lentiviral vector, combined with nonlethal irradiation provides a strong rationale for the development of gene therapy for WAS patients. ..
- Kobayashi R, Ariga T, Nonoyama S, Kanegane H, Tsuchiya S, Morio T, et al. Outcome in patients with Wiskott-Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan. Br J Haematol. 2006;135:362-6 pubmed..Given the improved outcome for WAS patients following transplantation from an unrelated donor, we conclude that patients with WAS should receive SCT as soon as possible after diagnosis. ..
- Symons M, Derry J, Karlak B, Jiang S, Lemahieu V, McCormick F, et al. Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell. 1996;84:723-34 pubmed..The WASP sequence contains two novel domains that are homologous to other proteins involved in action organization. ..
- Cory G, MacCarthy Morrogh L, Banin S, Gout I, Brickell P, Levinsky R, et al. Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways. J Immunol. 1996;157:3791-5 pubmed..In this work, we show binding of WASP to the Src homology 3 domains of Btk, Itk, Tec, Grb2, and phospholipase C-gamma, which suggests a function for WASP in lymphoid cell signaling. ..
- Lemahieu V, Gastier J, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14:54-66 pubmed..It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course. Studies at the transcript and protein level are needed for a better assessment. ..
- Kolluri R, Tolias K, Carpenter C, Rosen F, Kirchhausen T. Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42. Proc Natl Acad Sci U S A. 1996;93:5615-8 pubmed..Taken together these data suggest that the WAS protein might function as a signal transduction adaptor downstream of Cdc42, and in affected males, the cytoskeletal abnormalities may result from a defect in Cdc42 signaling. ..
- Badolato R, Sozzani S, Malacarne F, Bresciani S, Fiorini M, Borsatti A, et al. Monocytes from Wiskott-Aldrich patients display reduced chemotaxis and lack of cell polarization in response to monocyte chemoattractant protein-1 and formyl-methionyl-leucyl-phenylalanine. J Immunol. 1998;161:1026-33 pubmed..These results suggest that WAS protein is involved in the monocyte response to the chemokines MCP-1 and macrophage inflammatory protein-1alpha. ..
- Wu Y, Spencer S, Lasky L. Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein. J Biol Chem. 1998;273:5765-70 pubmed..These data suggest that the PSTPIP and WASP interaction is regulated by tyrosine phosphorylation of the PSTPIP SH3 domain, and this binding event may control aspects of the actin cytoskeleton. ..
- Jin Y, Mazza C, Christie J, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004;104:4010-9 pubmed..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. ..
- Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson D, et al. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001;166:5245-9 pubmed..This case might have significant implications regarding the prospects of the future gene therapy for WAS patients. ..
- Ho H, Rohatgi R, Lebensohn A, Li J, Gygi S, Kirschner M. Toca-1 mediates Cdc42-dependent actin nucleation by activating the N-WASP-WIP complex. Cell. 2004;118:203-16 pubmed publisher..These findings represent a significantly revised view of Cdc42-signaling and shed light on the pathogenesis of Wiskott-Aldrich syndrome...
- Park J, Kob M, Prodeus A, Rosen F, Shcherbina A, REMOLD O DONNELL E. Early deficit of lymphocytes in Wiskott-Aldrich syndrome: possible role of WASP in human lymphocyte maturation. Clin Exp Immunol. 2004;136:104-10 pubmed
- Jones G, Zicha D, Dunn G, Blundell M, Thrasher A. Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp. Int J Biochem Cell Biol. 2002;34:806-15 pubmed..Expression of exogenous WAS protein (WASp) in these cells also restored normal polarised cell morphology and the ability to form podosomes. ..
- Wada T, Konno A, Schurman S, Garabedian E, Anderson S, Kirby M, et al. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest. 2003;111:1389-97 pubmed..These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients. ..
- Badour K, Zhang J, Shi F, McGavin M, Rampersad V, Hardy L, et al. The Wiskott-Aldrich syndrome protein acts downstream of CD2 and the CD2AP and PSTPIP1 adaptors to promote formation of the immunological synapse. Immunity. 2003;18:141-54 pubmed
- Thrasher A. WASp in immune-system organization and function. Nat Rev Immunol. 2002;2:635-46 pubmed..Now, WASp has been shown to be intimately involved in many pathways that influence the function of the immune system. Disturbances in these systems result in the complex immunodysregulation of Wiskott-Aldrich syndrome. ..
- Banin S, Truong O, Katz D, Waterfield M, Brickell P, Gout I. Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases. Curr Biol. 1996;6:981-8 pubmed..Our data suggest that binding of Fyn to WASp may be a critical event in such signalling pathways in haematopoietic cells. ..
- Kolluri R, Shehabeldin A, Peacocke M, Lamhonwah A, Teichert Kuliszewska K, Weissman S, et al. Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum Mol Genet. 1995;4:1119-26 pubmed
- Lutskiy M, Sasahara Y, Kenney D, Rosen F, REMOLD O DONNELL E. Wiskott-Aldrich syndrome in a female. Blood. 2002;100:2763-8 pubmed
- Anton I, Lu W, Mayer B, Ramesh N, Geha R. The Wiskott-Aldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck. J Biol Chem. 1998;273:20992-5 pubmed..We demonstrate the presence of profilin in Nck precipitates suggesting that Nck may couple extracellular signals to the cytoskeleton via its interaction with WIP and profilin. ..
- Lutskiy M, Rosen F, REMOLD O DONNELL E. Genotype-proteotype linkage in the Wiskott-Aldrich syndrome. J Immunol. 2005;175:1329-36 pubmed..Knowledge of the molecular effect of mutations would aid also in identifying disease-modifying genes. ..
- Zhang J, Shehabeldin A, da Cruz L, Butler J, Somani A, McGavin M, et al. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J Exp Med. 1999;190:1329-42 pubmed..The data also reveal a role for WASp in modulating endocytosis and phagocytosis and, accordingly, suggest that the immune deficit conferred by WASp deficiency reflects the disruption of a broad range of cellular behaviors. ..
- Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, et al. Clinical course of patients with WASP gene mutations. Blood. 2004;103:456-64 pubmed..Based on data presented here, hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis. ..
- Aspenstrom P, Lindberg U, Hall A. Two GTPases, Cdc42 and Rac, bind directly to a protein implicated in the immunodeficiency disorder Wiskott-Aldrich syndrome. Curr Biol. 1996;6:70-5 pubmed..This observation, and the results presented here, suggest that WAS is the result of defects in signal transduction pathways regulated by Cdc42/Rac and Nck. ..
- Bouma G, Burns S, Thrasher A. Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells. Blood. 2007;110:4278-84 pubmed
- Cianferoni A, Massaad M, Feske S, de la Fuente M, Gallego L, Ramesh N, et al. Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2005;116:1364-71 pubmed..These defects underlie defective IL-2 expression and T-cell proliferation in WAS. ..
- Charrier S, Stockholm D, Seye K, Opolon P, Taveau M, Gross D, et al. A lentiviral vector encoding the human Wiskott-Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice. Gene Ther. 2005;12:597-606 pubmed..These data support further development of such lentiviral vectors for the gene therapy of WAS. ..
- Kim A, Kakalis L, Abdul Manan N, Liu G, Rosen M. Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein. Nature. 2000;404:151-8 pubmed..These data show that 'intrinsically unstructured' peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context. ..
- Facchetti F, Blanzuoli L, Vermi W, Notarangelo L, Giliani S, Fiorini M, et al. Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome. J Pathol. 1998;185:99-107 pubmed..As a whole, the degree of impairment of WASP protein expression in WAS/XLT seems to correlate with anomalies of cytoskeletal organization, strongly supporting a role for WASP in the regulation of F-actin polymerization. ..
- Humblet Baron S, Sather B, Anover S, Becker Herman S, Kasprowicz D, Khim S, et al. Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest. 2007;117:407-18 pubmed..Finally, WASp(+) Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS. ..
- Lorenzi R, Brickell P, Katz D, Kinnon C, Thrasher A. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood. 2000;95:2943-6 pubmed..Results also show that, in normal macrophages, WASp itself is actively recruited to the cup, suggesting that assembly of this specialized cytoskeletal structure is dependent on its expression. (Blood. 2000;95:2943-2946) ..
- Bear J, Rawls J, Saxe C. SCAR, a WASP-related protein, isolated as a suppressor of receptor defects in late Dictyostelium development. J Cell Biol. 1998;142:1325-35 pubmed..These data suggest that SCAR may be a conserved negative regulator of G protein-coupled signaling, and that it plays an important role in regulating the actin cytoskeleton. ..
- Du W, Kumaki S, Uchiyama T, Yachie A, Yeng Looi C, Kawai S, et al. A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient. Hum Mutat. 2006;27:370-5 pubmed..To our knowledge, this is the first report describing somatic mosaicism due to a second-site mutation in the initiation codon of any inherited disorders. ..
- Dupré L, Trifari S, Follenzi A, Marangoni F, Lain de Lera T, Bernad A, et al. Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Mol Ther. 2004;10:903-15 pubmed..The observation that lentiviral vector-mediated gene transfer results in correction of T cell defects in vitro supports their application for gene therapy in WAS patients. ..
- Klein C, Nguyen D, Liu C, Mizoguchi A, Bhan A, Miki H, et al. Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice. Blood. 2003;101:2159-66 pubmed..Our results provide proof of principle that the WAS-associated T-cell signaling defects can be improved upon transplantation of retrovirally transduced HSCs without overt toxicity and may encourage clinical gene therapy trials. ..
- Ochs H, Notarangelo L. Structure and function of the Wiskott-Aldrich syndrome protein. Curr Opin Hematol. 2005;12:284-91 pubmed
- Filipovich A, Stone J, Tomany S, Ireland M, Kollman C, Pelz C, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97:1598-603 pubmed..The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children. ..
- Orange J, Ramesh N, REMOLD O DONNELL E, Sasahara Y, Koopman L, Byrne M, et al. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A. 2002;99:11351-6 pubmed..Thus, WASp has an important function in NK cells. In patients with WASp mutations, the resulting NK cell defects are likely to contribute to their disease. ..
- Imai K, Nonoyama S, Ochs H. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003;3:427-36 pubmed