|
|
 Previous Article | Table of Contents | Next Article 
Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia: WASP Gene Mutations, Protein Expression, and Phenotype
Qili Zhu,
Chiaki Watanabe,
Ting Liu,
Diane Hollenbaugh,
R. Michael Blaese,
Steven B. Kanner,
Alejandro Aruffo, and
Hans D. Ochs
From the Division of Infectious Diseases, Immunology and Rheumatology, Department of Pediatrics, University of Washington School of Medicine, Seattle; Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA; and the Clinical Gene Therapy Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, MD.
Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT), caused by mutations of the WAS protein (WASP) gene, represent different phenotypes of the same disease. To demonstrate a phenotype/genotype correlation, we determined WASP gene mutations in 48 unrelated WAS families. Mutations included missense (20 families) and nonsense (eight) mutations located mostly in exons 1 to 4, and splice-site mutations (seven) and deletions and insertions (13) located preferentially in exons 7 to 11. Both genomic DNA and cDNA were sequenced and WASP expression was measured in cell lysates using peptide-specific rabbit anti-WASP antibodies. WASP was expressed in hematopoietic cell lines including bone marrow-derived CD34+ cells. Missense mutations located in exons 1 to 3 caused mild disease in all but one family and permitted WASP expression, although frequently at decreased concentration. Missense mutations affecting exon 4 were associated with classic WAS and, with one exception, barely detectable WASP. Nonsense mutations caused classic WAS and lack of protein. Insertions, deletions, and splice-site mutations resulted in classic WAS and absent, unstable, truncated, or multiply spliced protein. Using affinity precipitation, WASP was found to bind to Src SH3-containing proteins Fyn, Lck, PLC- , and Grb2, and mutated WASP, if expressed, was able to bind to Fyn-glutathione S-transferase (GST) fusion protein. We conclude that missense mutations affecting the PH domain (exons 1 to 3) of WASP inhibit less important functions of the protein and result in a mild phenotype, and that missense mutations affecting exon 4 and complex mutations affecting the 3' portion of WASP interfere with crucial functions of the protein and cause classic WAS.
Blood, Vol. 90 No. 7 (October 1), 1997:
pp. 2680-2689
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Bosticardo, F. Marangoni, A. Aiuti, A. Villa, and M. Grazia Roncarolo
Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome
Blood,
June 18, 2009;
113(25):
6288 - 6295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Astrakhan, H. D. Ochs, and D. J. Rawlings
Wiskott-Aldrich Syndrome Protein Is Required for Homeostasis and Function of Invariant NKT Cells
J. Immunol.,
June 15, 2009;
182(12):
7370 - 7380.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S. Westerberg, M. A. de la Fuente, F. Wermeling, H. D. Ochs, M. C. I. Karlsson, S. B. Snapper, and L. D. Notarangelo
WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function
Blood,
November 15, 2008;
112(10):
4139 - 4147.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. R. Davis, M. J. DiCola, N. L. Prokopishyn, J. B. Rosenberg, D. Moratto, L. M. Muul, F. Candotti, and R. Michael Blaese
Unprecedented diversity of genotypic revertants in lymphocytes of a patient with Wiskott-Aldrich syndrome
Blood,
May 15, 2008;
111(10):
5064 - 5067.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ozsahin, M. Cavazzana-Calvo, L. D. Notarangelo, A. Schulz, A. J. Thrasher, E. Mazzolari, M. A. Slatter, F. Le Deist, S. Blanche, P. Veys, et al.
Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation
Blood,
January 1, 2008;
111(1):
439 - 445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. T. Nurden and P. Nurden
Inherited thrombocytopenias
Haematologica,
September 1, 2007;
92(9):
1158 - 1164.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsuboi
Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages
J. Immunol.,
March 1, 2007;
178(5):
2987 - 2995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. David, C. Camacho-Hubner, A. Bhangoo, S. J. Rose, F. Miraki-Moud, S. A. Akker, G. E. Butler, S. Ten, P. E. Clayton, A. J. L. Clark, et al.
An Intronic Growth Hormone Receptor Mutation Causing Activation of a Pseudoexon Is Associated with a Broad Spectrum of Growth Hormone Insensitivity Phenotypes
J. Clin. Endocrinol. Metab.,
February 1, 2007;
92(2):
655 - 659.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Trifari, G. Sitia, A. Aiuti, S. Scaramuzza, F. Marangoni, L. G. Guidotti, S. Martino, P. Saracco, L. D. Notarangelo, M.-G. Roncarolo, et al.
Defective Th1 Cytokine Gene Transcription in CD4+ and CD8+ T Cells from Wiskott-Aldrich Syndrome Patients
J. Immunol.,
November 15, 2006;
177(10):
7451 - 7461.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tsuboi
A Complex of Wiskott-Aldrich Syndrome Protein with Mammalian Verprolins Plays an Important Role in Monocyte Chemotaxis.
J. Immunol.,
June 1, 2006;
176(11):
6576 - 6585.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Wada, S. H. Schurman, E. K. Garabedian, A. Yachie, and F. Candotti
Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome
Blood,
December 1, 2005;
106(12):
3895 - 3897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Lutskiy, F. S. Rosen, and E. Remold-O'Donnell
Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome
J. Immunol.,
July 15, 2005;
175(2):
1329 - 1336.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Huang, H. D. Ochs, B. Dupont, and Y. M. Vyas
The Wiskott-Aldrich Syndrome Protein Regulates Nuclear Translocation of NFAT2 and NF-{kappa}B (RelA) Independently of Its Role in Filamentous Actin Polymerization and Actin Cytoskeletal Rearrangement
J. Immunol.,
March 1, 2005;
174(5):
2602 - 2611.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. L. Ramprasad, A. Thool, S. Murugan, D. Nancarrow, P. Vyas, S. K. Rao, A. Vidhya, K. Ravishankar, and G. Kumaramanickavel
Truncating Mutation in the NHS Gene: Phenotypic Heterogeneity of Nance-Horan Syndrome in an Asian Indian Family
Invest. Ophthalmol. Vis. Sci.,
January 1, 2005;
46(1):
17 - 23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Jin, C. Mazza, J. R. Christie, S. Giliani, M. Fiorini, P. Mella, F. Gandellini, D. M. Stewart, Q. Zhu, D. L. Nelson, et al.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation
Blood,
December 15, 2004;
104(13):
4010 - 4019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Burns, G. O. Cory, W. Vainchenker, and A. J. Thrasher
Mechanisms of WASp-mediated hematologic and immunologic disease
Blood,
December 1, 2004;
104(12):
3454 - 3462.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Wada, S. H. Schurman, G. J. Jagadeesh, E. K. Garabedian, D. L. Nelson, and F. Candotti
Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family
Blood,
September 1, 2004;
104(5):
1270 - 1272.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Gismondi, L. Cifaldi, C. Mazza, S. Giliani, S. Parolini, S. Morrone, J. Jacobelli, E. Bandiera, L. Notarangelo, and A. Santoni
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,
July 15, 2004;
104(2):
436 - 443.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Imai, T. Morio, Y. Zhu, Y. Jin, S. Itoh, M. Kajiwara, J.-i. Yata, S. Mizutani, H. D. Ochs, and S. Nonoyama
Clinical course of patients with WASP gene mutations
Blood,
January 15, 2004;
103(2):
456 - 464.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Lacout, E. Haddad, S. Sabri, F. Svinarchouk, L. Garcon, C. Capron, A. Foudi, R. Mzali, S. B. Snapper, F. Louache, et al.
A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome
Blood,
August 15, 2003;
102(4):
1282 - 1289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dupuis-Girod, J. Medioni, E. Haddad, P. Quartier, M. Cavazzana-Calvo, F. Le Deist, G. de Saint Basile, J. Delaunay, K. Schwarz, J.-L. Casanova, et al.
Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients
Pediatrics,
May 1, 2003;
111(5):
e622 - 627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Lutskiy, Y. Sasahara, D. M. Kenney, F. S. Rosen, and E. Remold-O'Donnell
Wiskott-Aldrich syndrome in a female
Blood,
September 26, 2002;
100(8):
2763 - 2768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Rees, T. M. Lewis, J. B. J. Kwok, G. R. Mortier, P. Govaert, R. G. Snell, P. R. Schofield, and M. J. Owen
Hyperekplexia associated with compound heterozygote mutations in the {beta}-subunit of the human inhibitory glycine receptor (GLRB)
Hum. Mol. Genet.,
April 1, 2002;
11(7):
853 - 860.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. D. Notarangelo, C. Mazza, S. Giliani, C. D'Aria, F. Gandellini, C. Ravelli, M. G. Locatelli, D. L. Nelson, H. D. Ochs, and L. D. Notarangelo
Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia
Blood,
March 15, 2002;
99(6):
2268 - 2269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ariga, T. Kondoh, K. Yamaguchi, M. Yamada, S. Sasaki, D. L. Nelson, H. Ikeda, K. Kobayashi, H. Moriuchi, and Y. Sakiyama
Spontaneous In Vivo Reversion of an Inherited Mutation in the Wiskott-Aldrich Syndrome
J. Immunol.,
April 15, 2001;
166(8):
5245 - 5249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. G. Coppolino, M. Krause, P. Hagendorff, D. A. Monner, W. Trimble, S. Grinstein, J. Wehland, and A. S. Sechi
Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fc{gamma} receptor signalling during phagocytosis
J. Cell Sci.,
January 12, 2001;
114(23):
4307 - 4318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Haddad, J. L. Zugaza, F. Louache, N. Debili, C. Crouin, K. Schwarz, A. Fischer, W. Vainchenker, and J. Bertoglio
The interaction between Cdc42 and WASP is required for SDF-1-induced T-lymphocyte chemotaxis
Blood,
January 1, 2001;
97(1):
33 - 38.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yamada, T. Ariga, N. Kawamura, K. Yamaguchi, M. Ohtsu, D. L. Nelson, T. Kondoh, I. Kobayashi, M. Okano, K. Kobayashi, et al.
Determination of Carrier Status for the Wiskott-Aldrich Syndrome by Flow Cytometric Analysis of Wiskott-Aldrich Syndrome Protein Expression in Peripheral Blood Mononuclear Cells
J. Immunol.,
July 15, 2000;
165(2):
1119 - 1122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. H. Raskind, K. K. Niakan, J. Wolff, M. Matsushita, T. Vaughan, G. Stamatoyannopoulos, C. Watanabe, J. Rios, and H. D. Ochs
Mapping of a syndrome of X-linked thrombocytopenia with thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia
Blood,
April 1, 2000;
95(7):
2262 - 2268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Tian, D. L. Nelson, and D. M. Stewart
Cdc42-interacting Protein 4 Mediates Binding of the Wiskott-Aldrich Syndrome Protein to Microtubules
J. Biol. Chem.,
March 10, 2000;
275(11):
7854 - 7861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Rengan, H. D. Ochs, L. I. Sweet, M. L. Keil, W. T. Gunning, N. A. Lachant, L. A. Boxer, and G. M. Omann
Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells
Blood,
February 15, 2000;
95(4):
1283 - 1292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kanegane, K. Nomura, T. Miyawaki, Y. Sasahara, S. Kawai, S. Tsuchiya, G. Murakami, T. Futatani, and H. D. Ochs
X-linked thrombocytopenia identified by flow cytometric demonstration of defective Wiskott-Aldrich syndrome protein in lymphocytes
Blood,
February 1, 2000;
95(3):
1110 - 1111.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Linder, K Hufner, U Wintergerst, and M Aepfelbacher
Microtubule-dependent formation of podosomal adhesion structures in primary human macrophages
J. Cell Sci.,
January 12, 2000;
113(23):
4165 - 4176.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. S. Gross, J. I. Wilde, L. Quek, H. Chapel, D. L. Nelson, and S. P. Watson
Regulation and Function of WASp in Platelets by the Collagen Receptor, Glycoprotein VI
Blood,
December 15, 1999;
94(12):
4166 - 4176.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Shcherbina, F. S. Rosen, and E. Remold-O'Donnell
WASP Levels in Platelets and Lymphocytes of Wiskott-Aldrich Syndrome Patients Correlate with Cell Dysfunction
J. Immunol.,
December 1, 1999;
163(11):
6314 - 6320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. L. Rawlings, G. M. Crooks, D. Bockstoce, L. W. Barsky, R. Parkman, and K. I. Weinberg
Spontaneous Apoptosis in Lymphocytes From Patients With Wiskott-Aldrich Syndrome: Correlation of Accelerated Cell Death and Attenuated Bcl-2 Expression
Blood,
December 1, 1999;
94(11):
3872 - 3882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Haddad, E. Cramer, C. Riviere, P. Rameau, F. Louache, J. Guichard, D. L. Nelson, A. Fischer, W. Vainchenker, and N. Debili
The Thrombocytopenia of Wiskott Aldrich Syndrome Is Not Related to a Defect in Proplatelet Formation
Blood,
July 15, 1999;
94(2):
509 - 518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Stewart, L. Tian, and D. L. Nelson
Mutations That Cause the Wiskott-Aldrich Syndrome Impair the Interaction of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein
J. Immunol.,
April 15, 1999;
162(8):
5019 - 5024.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Baba, S. Nonoyama, M. Matsushita, T. Yamadori, S. Hashimoto, K. Imai, S. Arai, T. Kunikata, M. Kurimoto, T. Kurosaki, et al.
Involvement of Wiskott-Aldrich Syndrome Protein in B-Cell Cytoplasmic Tyrosine Kinase Pathway
Blood,
March 15, 1999;
93(6):
2003 - 2012.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. I. Johnson
Cdc42: An Essential Rho-Type GTPase Controlling Eukaryotic Cell Polarity
Microbiol. Mol. Biol. Rev.,
March 1, 1999;
63(1):
54 - 105.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Oda, H. D. Ochs, B. J. Druker, K. Ozaki, C. Watanabe, M. Handa, Y. Miyakawa, and Y. Ikeda
Collagen Induces Tyrosine Phosphorylation of Wiskott-Aldrich Syndrome Protein in Human Platelets
Blood,
September 15, 1998;
92(6):
1852 - 1858.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
