Clinical course of patients with WASP gene mutations.

Mutations of the Wiskott-Aldrich syndrome protein (WASP) gene result either in the classic Wiskott-Aldrich syndrome (WAS) or in a less severe form, X-linked thrombocytopenia (XLT). A phenotype-genotype correlation has been reported by some but not by other investigators. In this study, we characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive. In contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient was correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival and survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients. This analysis provides evidence for a strong phenotype-genotype correlation and demonstrates that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT. 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.

[1]  Michael K. Rosen,et al.  Autoinhibition and activation mechanisms of the Wiskott–Aldrich syndrome protein , 2000, Nature.

[2]  A. Bakkaloğlu,et al.  Henoch-Schönlein purpura in Wiskott-Aldrich syndrome , 2001, Pediatric Nephrology.

[3]  K. Sullivan,et al.  A multiinstitutional survey of the Wiskott-Aldrich syndrome. , 1994, The Journal of pediatrics.

[4]  C. Mathew,et al.  A variant of Wiskott-Aldrich syndrome with nephropathy is linked to DXS255. , 1995, Journal of medical genetics.

[5]  Adrian J. Thrasher,et al.  Wasp in immune-system organization and function , 2002, Nature Reviews Immunology.

[6]  T. Morio,et al.  Mutations of the WASP gene in 10 Japanese patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia. , 2000, International journal of hematology.

[7]  T. Hagemann,et al.  Gene regulation of Wiskott-Aldrich syndrome protein and the human homolog of the Drosophila Su(var)3-9: WASP and SUV39H1, two adjacent genes at Xp11.23. , 2000, Biochimica et biophysica acta.

[8]  J. V. Stone,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. , 2001, Blood.

[9]  U. Francke,et al.  The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. , 1995, Blood.

[10]  G. Capasso,et al.  IgA glomerulonephritis in Wiskott-Aldrich syndrome. , 1988, Child nephrology and urology.

[11]  A. Ducruix,et al.  Signalling to actin: the Cdc42-N-WASP-Arp2/3 connection. , 1999, Chemistry & biology.

[12]  O. Parolini,et al.  High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome. , 1995, Blood.

[13]  F. Finkelman,et al.  Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients. , 1997, Journal of immunology.

[14]  L. Harker,et al.  The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets , 1980 .

[15]  K. Yoshida,et al.  Epstein-Barr virus-associated malignant lymphoma with macroamylasemia and monoclonal gammopathy in a patient with Wiskott-Aldrich syndrome. , 1997, Pediatric hematology and oncology.

[16]  J. Feehally,et al.  IgA1 glycosylation and the pathogenesis of IgA nephropathy. , 2000, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[17]  D. Nelson,et al.  Somatic mosaicism in Wiskott–Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Kanner,et al.  Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. , 1997, Blood.

[19]  C. Kawakami,et al.  Kawasaki Disease in a Patient with Wiskott-Aldrich Syndrome: An Increase in the Platelet Count , 2003, International journal of hematology.

[20]  S. Tsuboi,et al.  Expression of human Wiskott–Aldrich syndrome protein in patients’ cells leads to partial correction of a phenotypic abnormality of cell surface glycoproteins , 2000, Gene Therapy.

[21]  L. Notarangelo,et al.  X–linked thrombocytopenia and Wiskott–Aldrich syndrome are allelic diseases with mutations in the WASP gene , 1995, Nature Genetics.

[22]  U. Francke,et al.  Novel mutations in the Wiskott‐Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes , 1999, Human mutation.

[23]  A. Meindl,et al.  Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product , 1996, Human Genetics.

[24]  M. Yamada,et al.  Spontaneous In Vivo Reversion of an Inherited Mutation in the Wiskott-Aldrich Syndrome1 , 2001, The Journal of Immunology.

[25]  K. Schwarz.  WASPbase: a database of WAS- and XLT-causing mutations. , 1996, Immunology today.

[26]  C. Terhorst,et al.  T cells of patients with the Wiskott-Aldrich syndrome have a restricted defect in proliferative responses. , 1993, Journal of immunology.

[27]  D. Gustafsson,et al.  Development of allergies and asthma in infants and young children with atopic dermatitis – a prospective follow‐up to 7 years of age , 2000, Allergy.

[28]  Laura M. Machesky,et al.  Scar1 and the related Wiskott–Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex , 1998, Current Biology.

[29]  L. Spitler,et al.  Nephropathy in the Wiskott-Aldrich syndrome. , 1980, Pediatrics.

[30]  U. Francke,et al.  Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. , 1994, Cell.

[31]  R. Blaese,et al.  Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. , 1993, Blood.

[32]  H. Ochs,et al.  Wiskott-aldrich syndrome , 2001, Current allergy and asthma reports.

[33]  K. Imai,et al.  X‐linked thrombocytopenia in a girl , 2002, British journal of haematology.

[34]  H. Ochs.  Ser ies The Wiskott-Aldrich Syndrome , 2002 .