Skip to main content

Advertisement

SpringerLink
Log in

Clinical Aspects and Genetic Analysis of Taiwanese Patients with Wiskott–Aldrich Syndrome Protein Mutation: The First Identification of X-Linked Thrombocytopenia in the Chinese with Novel Mutations

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Background

Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants.

Methods

Clinical manifestations, immunologic functions, and WASP gene sequencing and expressions were analyzed in WAS patients. And, those patients with idiopathic thrombocytopenic purpura and “small” thrombocytopenia were enrolled.

Results

Of 16 patients studied in 1993–2009, 12 presented as classic WAS phenotype and four had X-linked thrombocytopenia (XLT). Almost all correlated to the WASP expression level and severity of infections. Causes of mortality in the 12 classic WAS patients were mass bleeding, Staphylococcus aureus sepsis, and cytomegalovirus (CMV) pneumonitis in three non-transplant cases, and EBV-associated lymphoproliferative disorder and CMV pneumonitis in two non-engrafted transplant patients. Splicing mutations of Int 8 (+5) G>A in cousins and insertion of 1023 C in unrelated families presented as both XLT and classic WAS phenotype in the same mutations. Four XLT patients, including two novel mutations of 1023 Ins C (in 2) and “double” missense mutations of 1378 C>T and 1421 T>C had relatively higher CD4+ memory cells and/or activated lymphocytes (CD3+CD69+) compared with those of classic WAS patients.

Conclusions

The lower ratio of XLT to classic WAS patients underestimates the burden of Taiwanese patients with WASP mutations, especially the XLT phenotype. A clustering pattern on exon 1 and five unique mutations (deletion of 45-48 ACCA, IVS 1 (−1) G>C, large deletion of promoter and exon 1 and 2, insertion 1023 C, and 1378 C>T and 1421 T>C) explain the genetic variations in different ethnic groups, despite the possibility of selection and ascertainment bias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wiskott A. Familiarer, angeborener Morbus Werlhofii? Monatsschr Kinderheilkd. 1937;68:212–6.

    Google Scholar 

  2. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multi-institutional survey of the Wiskott–Aldrich syndrome. J Pediatr. 1994;125:876–85.

    Article  CAS  PubMed  Google Scholar 

  3. Perry GS 3rd, Spector BD, Schuman LM, Mandel JS, Anderson VE, McHugh RB, et al. The Wiskott–Aldrich syndrome in the United States and Canada (1892–1979). J Pediatr. 1980;97:72–8.

    Article  PubMed  Google Scholar 

  4. Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott–Aldrich syndrome. Cell. 1994;78:635–44.

    Article  CAS  PubMed  Google Scholar 

  5. Ochs HD, Thrasher AJ. The Wiskott–Aldrich syndrome. J Allergy Clin Immunol. 2006;117:725–38.

    Article  CAS  PubMed  Google Scholar 

  6. Bosticardo M, Marangoni F, Aiuti A, Villa A, Grazia Roncarolo M. Recent advances in understanding the pathophysiology of Wiskott–Aldrich syndrome. Blood. 2009;113:6288–95.

    Article  CAS  PubMed  Google Scholar 

  7. Wengler GS, Notarangelo LD, Berardelli S, Pollonni G, Mella P, Fasth A, et al. High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott–Aldrich syndrome. Blood. 1995;86:3648–54.

    CAS  PubMed  Google Scholar 

  8. Zhu Q, Watanabe C, Liu T, Hollenbaugh D, Blaese RM, Kanner SB, et al. Wiskott–Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood. 1997;90:2680–9.

    CAS  PubMed  Google Scholar 

  9. Lemahieu V, Gastier JM, 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Schindelhauer D, Weiss M, Hellebrand H, Golla A, Hergersberg M, Seger R, 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. Hum Genet. 1996;98:68–76.

    Article  CAS  PubMed  Google Scholar 

  12. Proust A, Guillet B, Picard C, de Saint Basile G, Pondarre C, Tamary H, et al. Detection of 28 novel mutations in the Wiskott–Aldrich syndrome and X-linked thrombocytopenia based on multiplex PCR. Blood Cells Mol Dis. 2007;39:102–6.

    Article  CAS  PubMed  Google Scholar 

  13. Imai K, Nonoyama S, Ochs HD. WASP (Wiskott–Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003;3:427–36.

    Article  CAS  PubMed  Google Scholar 

  14. Jin Y, Mazza C, Christie JR, 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.

    Article  CAS  PubMed  Google Scholar 

  15. Tong YH, Sinniah D, Murugasu R, White JC. Two Malaysian Chinese male children with the Wiskott–Aldrich syndrome. Singapore Med J. 1979;20:355–9.

    CAS  PubMed  Google Scholar 

  16. Lin CY, Hsu HC. Acute immune complex mediated glomerulonephritis in a Chinese girl with Wiskott–Aldrich syndrome variant. Ann Allergy. 1984;53:74–8.

    CAS  PubMed  Google Scholar 

  17. Lau YL, Jones BM, Low LC, Wong SN, Leung NK. Defective B-cell and regulatory T-cell function in Wiskott–Aldrich syndrome. Eur J Pediatr. 1992;151:680–3.

    Article  CAS  PubMed  Google Scholar 

  18. Lau YL, Wong SN, Lawton WM. Takayasu's arteritis associated with Wiskott–Aldrich syndrome. J Paediatr Child Health. 1992;28:407–9.

    Article  CAS  PubMed  Google Scholar 

  19. Huang MT, Chou CC, Jou ST, Lin KH, Hsieh KH. Successful bone marrow transplantation in a Chinese boy with Wiskott–Aldrich syndrome. Asian Pac J Allergy Immunol. 1996;14:57–63.

    CAS  PubMed  Google Scholar 

  20. Chien YH, Hwu WL, Ariga T, Chang KW, Yang YH, Lin KH, et al. Molecular diagnosis of Wiskott–Aldrich syndrome in Taiwan. J Microbiol Immunol Infect. 2004;37:276–81.

    PubMed  Google Scholar 

  21. Lee WI, Yang CY, Jaing TH, Huang JL, Chien YH, Chang KW. Clinical aspects and molecular analysis of Chinese patients with Wiskott–Aldrich syndrome in Taiwan. Int Arch Allergy Immunol. 2008;145:15–23.

    Article  CAS  PubMed  Google Scholar 

  22. Lee PP, Chen TX, Jiang LP, Chen J, Chan KW, Lee TL, et al. Clinical and molecular characteristics of 35 Chinese children with Wiskott–Aldrich syndrome. J Clin Immunol. 2009;29:490–500.

    Article  CAS  PubMed  Google Scholar 

  23. Ozsahin H, Cavazzana-Calvo M, Notarangelo LD, Schulz A, Thrasher AJ, Mazzolari E, 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. 2008;111:439–45.

    Article  CAS  PubMed  Google Scholar 

  24. Liang FC, Wei YC, Jiang TH, Hsiehi MY, Wen YC, Chiou YS, et al. Current classification and status of primary immunodeficiency diseases in Taiwan. Acta Paediatr Taiwan. 2008;49:3–8.

    PubMed  Google Scholar 

  25. Zhu Q, Zhang M, Blaese RM, Derry JM, Junker A, Francke U, et al. The Wiskott–Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. Blood. 1995;86:3797–804.

    CAS  PubMed  Google Scholar 

  26. Ochs HD. The Wiskott–Aldrich syndrome. Isr Med Assoc J. 2002;4:379–84.

    CAS  PubMed  Google Scholar 

  27. Lee WI, Kuo ML, Huang JL, Lin SJ, Wu CJ. Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period. J Clin Immunol. 2005;18:162–72.

    Article  Google Scholar 

  28. Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood. 2005;105:1881–90.

    Article  CAS  PubMed  Google Scholar 

  29. Stewart DM, Treiber-Held S, Kurman CC, Facchetti F, Notarangelo LD, Nelson DL. Studies of the expression of the Wiskott–Aldrich syndrome protein. J Clin Invest. 1996;97:2627–34.

    Article  CAS  PubMed  Google Scholar 

  30. Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL, et al. Somatic mosaicism in Wiskott–Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci USA. 2001;98:8697–702.

    Article  CAS  PubMed  Google Scholar 

  31. Jaing TH, Tsai BY, Chen SH, Lee WI, Chang KW, Chu SM. Early transplantation of unrelated cord blood in a two-month-old infant with Wiskott–Aldrich syndrome. Pediatr Transplant. 2007;11:557–9.

    Article  PubMed  Google Scholar 

  32. Burns S, Cory GO, Vainchenker W, Thrasher AJ. Mechanisms of WASp-mediated hematologic and immunologic disease. Blood. 2004;104:3454–62.

    Article  CAS  PubMed  Google Scholar 

  33. Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol. 2002;2:635–46.

    Article  CAS  PubMed  Google Scholar 

  34. Ochs HD, Slichter SJ, Harker LA, Von Behrens WE, Clark RA, Wedgwood RJ. The Wiskott–Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood. 1980;55:243–52.

    CAS  PubMed  Google Scholar 

  35. Park JY, Kob M, Prodeus AP, Rosen FS, 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.

    Article  CAS  PubMed  Google Scholar 

  36. Adriani M, Aoki J, Horai R, Thornton AM, Konno A, Kirby M, et al. Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome. Clin Immunol. 2007;124:41–8.

    Article  CAS  PubMed  Google Scholar 

  37. Humblet-Baron S, Sather B, Anover S, Becker-Herman S, Kasprowicz DJ, Khim S, et al. Wiskott–Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest. 2007;117:407–18.

    Article  CAS  PubMed  Google Scholar 

  38. Maillard MH, Cotta-de-Almeida V, Takeshima F, Nguyen DD, Michetti P, Nagler C, et al. The Wiskott–Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med. 2007;204:381–91.

    Article  CAS  PubMed  Google Scholar 

  39. Marangoni F, Trifari S, Scaramuzza S, Panaroni C, Martino S, Notarangelo LD, et al. WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J Exp Med. 2007;204:369–80.

    Article  CAS  PubMed  Google Scholar 

  40. Astrakhan A, Ochs HD, Rawlings DJ. Wiskott–Aldrich syndrome protein is required for homeostasis and function of invariant NKT cells. J Immunol. 2009;182:7370–80.

    Article  CAS  PubMed  Google Scholar 

  41. Stiehm RE, Ochd HD, Winkelstein JA. Immunologic disorders in infants and children. 5th ed. Philadelphia: Philadelphia; 2004.

    Google Scholar 

  42. Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112:973–80.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank all of the patients and their families for their cooperation, as well as their doctors for the referrals: Bor-Luen Chiang MD, Ph.D., and Yao-Hsu Yang M.D., Ph.D., of the National Taiwan University Hospital; Shyh-Dar Shyur M.D. of MacKay Memorial Hospital; Chung-Kai Chung M.D., of China Medical University Hospital; and Shyh-Shyn Chiou M.D., Ph.D., of Kaoshing University Hospital.

Author information

Authors and Affiliations

  1. Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial & Children’s Hospital and University College of Medicine, #5 Fu-Shing St. (Pediatric Office 12 L), Kwei-Shan, Taoyuan, Taiwan

    Wen-I Lee

  2. Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial & Children’s Hospital and University College of Medicine, Taoyuan, Taiwan

    Wen-I Lee & Jing-Long Huang

  3. Department of Pediatric Allergy, Immunology and Rheumatology, Chang Gung Memorial & Children’s Hospital and University College of Medicine, Taoyuan, Taiwan

    Wen-I Lee & Jing-Long Huang

  4. Department of Pediatric Hematology and Oncology, China Medical University, Taichung, Taiwan

    Kang-Hsi Wu

  5. Department of Pediatric Hematology and Oncology, Chang Gung Memorial & Children’s Hospital and University College of Medicine, Taoyuan, Taiwan

    Tang-Her Jaing

  6. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

    Yin-Hsiu Chien

  7. Department of Pediatric Gastroenterology Chang Gung Memorial & Children’s Hospital and University College of Medicine, Taoyuan, Taiwan

    Kuei-Wen Chang

Authors
  1. Wen-I Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing-Long Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tang-Her Jaing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kang-Hsi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yin-Hsiu Chien
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuei-Wen Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wen-I Lee.

Additional information

Disclosure

This study was supported by grants from the Chang-Gung Medical Research Progress (CMRPG 32069 and 450021) and the National Science Council (96-2314-B-182A-053-MY2).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, WI., Huang, JL., Jaing, TH. et al. Clinical Aspects and Genetic Analysis of Taiwanese Patients with Wiskott–Aldrich Syndrome Protein Mutation: The First Identification of X-Linked Thrombocytopenia in the Chinese with Novel Mutations. J Clin Immunol 30, 593–601 (2010). https://doi.org/10.1007/s10875-010-9381-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-010-9381-x

Keywords

Search

Navigation