Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Unexpected and variable phenotypes in a family with JAK3 deficiency

Genes & Immunity volume 2, pages 422–432 (2001)Cite this article

Abstract

Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID). We now report a family whose JAK3 mutations are associated with the persistence of circulating T cells, resulting in previously undescribed clinical presentations, ranging from a nearly unaffected 18-year-old subject to an 8-year-old sibling with a severe lymphoproliferative disorder. Both siblings were found to be compound heterozygotes for the same deleterious JAK3 mutations: an A96G initiation start site mutation, resulting in a dysfunctional, truncated protein product and a G2775(+3)C mutation in the splice donor site sequence of intron 18, resulting in a splicing defect and a predicted premature stop. These mutations were compatible with minimal amounts of functional JAK3 expression, leading to defective cytokine-dependent signaling. Activated T cells in these patients failed to express Fas ligand (FasL) in response to IL-2, which may explain the accumulation of T cells with an activated phenotype and a skewed T cell receptor (TcR) Vβ family distribution. We speculate that residual JAK3 activity accounted for the maturation of thymocytes, but was insufficient to sustain IL-2-mediated homeostasis of peripheral T cells via Fas/FasL interactions. These data demonstrate that the clinical spectrum of JAK3 deficiency is quite broad and includes immunodeficient patients with accumulation of activated T cells, and indicate an essential role for JAK3 in the homeostasis of peripheral T cells in humans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Leonard WJ, O’Shea JJ Jaks and STATs: biological implications Annu Rev Immunol 1998 16 293–322

    Article  CAS  PubMed  Google Scholar 

  2. Ihle JN, Thierfelder W, Teglund S et al Signaling by the cytokine receptor superfamily Ann NY Acad Sci 1998 865 1–9

    Article  CAS  PubMed  Google Scholar 

  3. Macchi P, Villa A, Giliani S et al Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) Nature 1995 377 65–68

    Article  CAS  PubMed  Google Scholar 

  4. Russell SM, Tayebi N, Nakajima H et al Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development Science 1995 270 797–800

    Article  CAS  PubMed  Google Scholar 

  5. Candotti F, Oakes SA, Johnston JA et al Structural and functional basis for JAK3-deficient severe combined immunodeficiency Blood 1997 90 3996–4003

    CAS  PubMed  Google Scholar 

  6. Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3 Science 1995 270 794–797

    Article  CAS  PubMed  Google Scholar 

  7. Nosaka T, van Deursen JM, Tripp RA et al Defective lymphoid development in mice lacking Jak3 Science 1995 270 800–802

    Article  CAS  PubMed  Google Scholar 

  8. Park SY, Saijo K, Takahashi T et al Developmental defects of lymphoid cells in Jak3 kinase-deficient mice Immunity 1995 3 771–782

    Article  CAS  PubMed  Google Scholar 

  9. Peschon JJ, Morrissey PJ, Grabstein KH et al Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice J Exp Med 1994 180 1955–1960

    Article  CAS  PubMed  Google Scholar 

  10. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine J Exp Med 1995 181 1519–1526

    Article  CAS  PubMed  Google Scholar 

  11. Puel A, Ziegler SF, Buckley RH, Leonard WJ Defective IL7R expression in T(−) B(+)NK(+) severe combined immunodeficiency Nat Genet 1998 20 394–397

    Article  CAS  PubMed  Google Scholar 

  12. Kennedy MK, Glaccum M, Brown SN et al Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice J Exp Med 2000 191 771–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Suzuki H, Kundig TM, Furlonger C et al Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta Science 1995 268 1472–1476

    Article  CAS  PubMed  Google Scholar 

  14. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment Immunity 1995 3 521–530

    Article  CAS  PubMed  Google Scholar 

  15. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting Nature 1991 352 621–624

    Article  CAS  PubMed  Google Scholar 

  16. Saijo K, Park SY, Ishida Y, Arase H, Saito T Crucial role of Jak3 in negative selection of self-reactive T cells J Exp Med 1997 185 351–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Baird AM, Lucas JA, Berg LJ A profound deficiency in thymic progenitor cells in mice lacking Jak3 J Immunol 2000 165 3680–3688

    Article  CAS  PubMed  Google Scholar 

  18. Brugnoni D, Notarangelo LD, Sottini A et al Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase Blood 1998 91 949–955

    CAS  PubMed  Google Scholar 

  19. McVay LD, Carding SR Generation of human gammadelta T-cell repertoires Crit Rev Immunol 1999 19 431–460

    CAS  PubMed  Google Scholar 

  20. Sottini A, Quiros-Roldan E, Albertini A, Primi D, Imberti L Assessment of T-cell receptor beta-chain diversity by heteroduplex analysis Hum Immunol 1996 48 12–22

    Article  CAS  PubMed  Google Scholar 

  21. Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death Immunity 1999 11 281–288

    Article  CAS  PubMed  Google Scholar 

  22. Fischer A, Rieux-Laucat F, Le Deist F Autoimmune lymphoproliferative syndromes (ALPS): models for the study of peripheral tolerance Rev Immunogenet 2000 2 52–60

    CAS  PubMed  Google Scholar 

  23. Buckley RH, Schiff RI, Schiff SE et al Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants J Pediatr 1997 130 378–387

    Article  CAS  PubMed  Google Scholar 

  24. Chen M, Cheng A, Chen YQ et al The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals Proc Natl Acad Sci USA 1997 94 6910–6915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cacalano NA, Migone TS, Bazan F et al Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain Embo J 1999 18 1549–1558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hirschhorn R, Yang DR, Puck JM, Huie ML, Jiang CK, Kurlandsky LE Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency Nat Genet 1996 13 290–295

    Article  CAS  PubMed  Google Scholar 

  27. Stephan V, Wahn V, Le Deist F et al Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells N Engl J Med 1996 335 1563–1567

    Article  CAS  PubMed  Google Scholar 

  28. Schmalstieg FC, Leonard WJ, Noguchi M et al Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency J Clin Invest 1995 95 1169–1173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sharfe N, Shahar M, Roifman CM An interleukin-2 receptor gamma chain mutation with normal thymus morphology J Clin Invest 1997 100 3036–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mella P, Imberti L, Brugnoni D et al Development of autologous T lymphocytes in two males with X-linked severe combined immune deficiency: molecular and cellular characterization Clin Immunol 2000 95 39–50

    Article  CAS  PubMed  Google Scholar 

  31. Gozalo-Sanmillan S, McNally JM, Lin MY, Chambers CA, Berg LJ Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice J Immunol 2001 166 727–730

    Article  CAS  PubMed  Google Scholar 

  32. Baird AM, Thomis DC, Berg LJ T cell development and activation in Jak3-deficient mice J Leukoc Biol 1998 63 669–677

    Article  CAS  PubMed  Google Scholar 

  33. Thomis DC, Berg LJ Peripheral expression of Jak3 is required to maintain T lymphocyte function J Exp Med 1997 185 197–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thomis DC, Lee W, Berg LJ T cells from Jak3-deficient mice have intact TCR signaling, but increased apoptosis J Immunol 1997 159 4708–4719

    CAS  PubMed  Google Scholar 

  35. Vockley J, Rinaldo P, Bennett MJ, Matern D, Vladutiu GD Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways Mol Genet Metab 2000 71 10–18

    Article  CAS  PubMed  Google Scholar 

  36. Brown MP, Nosaka T, Tripp RA et al Reconstitution of early lymphoid proliferation and immune function in Jak3-deficient mice by interleukin-3 Blood 1999 94 1906–1914

    CAS  PubMed  Google Scholar 

  37. Moriggl R, Topham DJ, Teglund S et al Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells Immunity 1999 10 249–259

    Article  CAS  PubMed  Google Scholar 

  38. Lenardo M, Chan KM, Hornung F et al Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment Annu Rev Immunol 1999 17 221–253

    Article  CAS  PubMed  Google Scholar 

  39. Sharfe N, Dadi HK, Shahar M, Roifman CM Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor Proc Natl Acad Sci USA 1997 94 3168–3171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Candotti F, Oakes SA, Johnston JA, Notarangelo LD, O’Shea JJ, Blaese RM In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction J Exp Med 1996 183 2687–2692

    Article  CAS  PubMed  Google Scholar 

  41. Bunting KD, Sangster MY, Ihle JN, Sorrentino BP Restoration of lymphocyte function in Janus kinase 3-deficient mice by retroviral-mediated gene transfer Nat Med 1998 4 58–64

    Article  CAS  PubMed  Google Scholar 

  42. Sneller MC, Wang J, Dale JK et al Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis Blood 1997 89 1341–1348

    CAS  PubMed  Google Scholar 

  43. Rowen L, Koop BF, Hood L The complete 685-kilobase DNA sequence of the human beta T cell receptor locus Science 1996 272 1755–1762

    Article  CAS  PubMed  Google Scholar 

  44. Johnston JA, Kawamura M, Kirken RA et al Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2 Nature 1994 370 151–153

    Article  CAS  PubMed  Google Scholar 

  45. Kawamura M, McVicar DW, Johnston JA et al Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes Proc Natl Acad Sci USA 1994 91 6374–6378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu X, Robinson GW, Gouilleux F, Groner B, Hennighausen L Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue Proc Natl Acad Sci USA 1995 92 8831–8835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Drs Silvia Giliani, Donna M Krasnewich, Makoto Otsu, and Shepherd Schurman for helpful discussions, and Dr Stefania Pittaluga for her advice in evaluating histological samples.

Author information

Author notes

  1. G Morgan

    Present address: Medical Research Council Laboratories, PO Box 273, Banjul, West Africa, The Gambia

  2. EJA Gerritsen

    Present address: Department of Pediatrics, Medical Center Rijnmond-South, Rotterdam, The Netherlands

Authors and Affiliations

  1. Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, Bethesda, MD, USA

    DM Frucht, M Gadina, I Aksentijevich, K Takada, J Nelson & JJ O’Shea

  2. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD, USA

    GJ Jagadeesh, LM Muul & F Candotti

  3. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    JJH Bleesing & TA Fleisher

  4. Derriford Hospital, Plymouth, UK

    G Perham & ER Kaminski

  5. Great Ormond Street Hospital, London, UK

    G Morgan, EJA Gerritsen & PA Veys

  6. Department of Pediatrics, University of Brescia, Italy

    RF Schumacher, P Mella & LD Notarangelo

Authors
  1. DM Frucht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Gadina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. GJ Jagadeesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Aksentijevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. JJH Bleesing
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. LM Muul
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Perham
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. EJA Gerritsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. RF Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Mella
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. PA Veys
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. TA Fleisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. ER Kaminski
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. LD Notarangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. JJ O’Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. F Candotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to DM Frucht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frucht, D., Gadina, M., Jagadeesh, G. et al. Unexpected and variable phenotypes in a family with JAK3 deficiency . Genes Immun 2, 422–432 (2001). https://doi.org/10.1038/sj.gene.6363802

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363802

Keywords

This article is cited by

Search

Advanced search

Quick links