Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) (original) (raw)

Nature volume 377, pages 65–68 (1995)Cite this article

Abstract

SEVERE combined immune deficiency (SCID) represents a hetero-genous group of hereditary diseases. Mutations in the common γ-chain (γc), which is part of several cytokine receptors including those for interleukin (IL)-2, IL-4, IL-7, IL-9 and FL-15, are responsible for X-linked SCID1,2, which is usually associated with a lack of circulating T cells and the presence of B lymphocytes (T- B+ SCID). The gene(s) responsible for autosomal recessive T- B+ SCID is still unknown. The Jak-3 protein kinase3,4 has been found to associate with the γc-chain-containing cytokine receptors4–9. Therefore Jak-3 or other STAT proteins with which it interacts10,11 are candidate genes for autosomal recessive T- B+SCID7. Here we investigate two unrelated T- B+SCID patients (both from consanguineous parents) who have homozygous mutations in the gene for Jak-3. One patient carries a mutation (TyrlOO→Cys) in a conserved tyrosine residue in the JH7 domain of Jak-3 which is absent in more than 150 investigated chromosomes. The other patient carries a homozygous 151-base-pair deletion in the kinase-like domain, leading to a frameshift and premature termination. Both mutations resulted in markedly reduced levels of Jak-3. These findings show that abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Noguchi, M. et al. Cell 73, 147–157 (1993).
    Article CAS Google Scholar
  2. Schmaistieg, F. C. et al. J. clin. Invest. 95, 1169–1173 (1995).
    Article Google Scholar
  3. Kawamura, M. et al. Proc. natn. Acad. Sci. U.S.A. 91, 6374–6378 (1994).
    Article ADS CAS Google Scholar
  4. Witthuhn, B. A. et al. Nature 370, 153–157 (1994).
    Article ADS CAS Google Scholar
  5. Johnston, J. A. et al. Nature 370, 151–153 (1994).
    Article ADS CAS Google Scholar
  6. Boussiotis, V. A. et el. Science 266, 1039–1042 (1994).
    Article ADS CAS Google Scholar
  7. Russell, S. M. Science 266, 1042–1045 (1994).
    Article ADS CAS Google Scholar
  8. Myazaki, T. et al. Science 266, 1045–1047 (1994).
    Article ADS Google Scholar
  9. Musso, T. et al. J. exp. Med. 181, 1425–1431 (1995).
    Article CAS Google Scholar
  10. Darnell, J. E., Kerr, I. M. & Start, G. R. Science 264, 1415–1421 (1994).
    Article ADS CAS Google Scholar
  11. Ihle, J. N. & Kerr, I. M. Trends Genet. 11, 69–74 (1995).
    Article CAS Google Scholar
  12. Cao, X. et al. Immunity 2, 223–238 (1995).
    Article CAS Google Scholar
  13. Di Santo, J. P., Muller, W., Guy-Grand, D., Fischer, A. & Rajewsky, K. Proc. natn. Acad. Sci. U.S.A. 93, 377–381 (1995).
    Article ADS Google Scholar
  14. Gougeon, M.-L. et al. J. Immun. 145, 2873–2877 (1990).
    CAS PubMed Google Scholar
  15. Wengler, G. S., Allen, R. C., Parolini, O., Smith, H. & Conley, M. E. J. Immun. 150, 700–704 (1993).
    CAS PubMed Google Scholar
  16. Puck, J. M., Nussbaum, R. L. & Conley M. E. J. clin. Invest. 79, 1395–1400 (1987).
    Article CAS Google Scholar
  17. Conley, M. E. et al. Proc. natn. Acad. Sci. U.S.A. 85, 3090–3094 (1988).
    Article ADS CAS Google Scholar
  18. Chomczynski, P. & Sacchi, N. Analyt. Biochem. 162, 156–159 (1987).
    Article CAS Google Scholar
  19. Villa, A. et al. Nature Genet. 9, 414–417 (1995).
    Article CAS Google Scholar

Download references

Author information

Author notes

  1. Anna Villa: To whom correspondence should be addressed.

Authors and Affiliations

  1. Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, via Ampère 56, Milano, Italy
    Paolo Macchi, Anna Villa, Maria G. Sacco, Annalisa Frattini & Paolo Vezzoni
  2. Dipartimento Materno-lnfantile, Università di Brescia, Brescia, Italy
    Silvia Giliani, Fulvio Porta, Alberto G. Ugazio & Luigi D. Notarangelo
  3. Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis, Musculoskeletal and Skin diseases,
    James A. Johnston & John J. O'Sheai
  4. Clinical Gene Therapy Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland, 20892, USA
    Fabio Candotti

Authors

  1. Paolo Macchi
    You can also search for this author inPubMed Google Scholar
  2. Anna Villa
    You can also search for this author inPubMed Google Scholar
  3. Silvia Giliani
    You can also search for this author inPubMed Google Scholar
  4. Maria G. Sacco
    You can also search for this author inPubMed Google Scholar
  5. Annalisa Frattini
    You can also search for this author inPubMed Google Scholar
  6. Fulvio Porta
    You can also search for this author inPubMed Google Scholar
  7. Alberto G. Ugazio
    You can also search for this author inPubMed Google Scholar
  8. James A. Johnston
    You can also search for this author inPubMed Google Scholar
  9. Fabio Candotti
    You can also search for this author inPubMed Google Scholar
  10. John J. O'Sheai
    You can also search for this author inPubMed Google Scholar
  11. Paolo Vezzoni
    You can also search for this author inPubMed Google Scholar
  12. Luigi D. Notarangelo
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Macchi, P., Villa, A., Giliani, S. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).Nature 377, 65–68 (1995). https://doi.org/10.1038/377065a0

Download citation