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.

  • Letter
  • Published:

Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse

Nature Genetics volume 27, pages 68–73 (2001)Cite this article

Abstract

Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16–25 days after birth, and is characterized by overproliferation of CD4+CD8– T lymphocytes, extensive multiorgan infiltration and elevation of numerous cytokines1,2,3,4. Similar to animals that lack expression of either Ctla-4 (refs. 5,6) or Tgf-β (refs. 7,8), the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8– T-cell activity3,9. Here we identify the gene defective in sf mice by combining high-resolution genetic and physical mapping with large-scale sequence analysis. The protein encoded by this gene (designated Foxp3) is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Physical map of the sf region, genomic organization of Foxp3 and the sf mutation.
Figure 2: Analysis of Foxp3 transgenic mice.
Figure 3: Diminished T-cell numbers in lymph nodes from transgenic mice.
Figure 4: Tissue distribution of Foxp3 expression.
Figure 5: Mouse and human scurfin proteins contain a highly conserved forkhead domain.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Lyon, M., Peters, J., Glenister, P., Ball, S. & Wright, E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome . Proc. Natl. Acad. Sci. USA 87, 2433– 2437 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kanangat, S. et al. Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. Eur. J. Immunol. 26, 161–165 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Blair, P. et al. CD4+CD8– T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153, 3764–3774 (1994).

    CAS  PubMed  Google Scholar 

  4. Clark, L. et al. Cellular and molecular characterization of the scurfy mouse mutant . J. Immunol. 162, 2546– 2554 (1999).

    CAS  PubMed  Google Scholar 

  5. Tivol, E. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541– 547 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985– 988 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Shull, M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kulkarni, A. et al. Transforming growth factor β 1 null mutation in mice causes excessive inflammatory response and early death. Proc. Natl. Acad. Sci. USA 90, 770–774 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Godfrey, V., Rouse, B. & Wilkinson, J. Transplantation of T cell-mediated, lymphoreticular disease from the scurfy (sf) mouse. Am. J. Pathol. 145, 281–286 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Blair, P. et al. The mouse scurfy (sf) mutation is tightly linked to Gata1 and Tfe3 on the proximal X chromosome. Mamm. Genome 5, 652–654 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  11. Means, G., Toy, D., Baum, P. & Derry, J. A transcript map of a 2-Mb BAC contig in the proximal portion of the mouse X chromosome and regional mapping of the scurfy mutation. Genomics 65 , 213–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Kaestner, K., Knochel, W. & Martinez, D. Unified nomenclature for the winged- helix/forkhead transcription factors. Genes Dev. 14, 142 –146 (2000).

    CAS  PubMed  Google Scholar 

  13. Hong, N. et al. A targeted mutation at the T-cell receptor α/δ locus impairs T-cell development and reveals the presence of the nearby antiapoptosis gene Dad1. Mol. Cell. Biol. 17, 2151– 2157 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boyd, Y. et al. Mouse X chromosome. Mamm. Genome 7, S313–326 (1997).

    Article  Google Scholar 

  15. Schindelhauer, D. et al. Long-range map of a 3.5-Mb region in Xp11. 23–22 with a sequence-ready map from a 1.1-Mb gene-rich interval. Genome Res. 6, 1056–1069 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  16. Li, C. & Tucker, P. DNA-binding properties and secondary structural model of the hepatocyte nuclear factor 3/forkhead domain. Proc. Natl. Acad. Sci. USA 90, 11583– 11587 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Clark, K., Halay, E., Lai, E. & Burley, S. Co-crystal structure of the HNF-3/forkhead DNA-recognition motif resembles histone H5. Nature 364, 412–420 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  18. Wildin, R.S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 ( 2001).

    Article  CAS  PubMed  Google Scholar 

  19. Qian, X. & Costa, R. Analysis of hepatocyte nuclear factor-3b protein domains required for transcriptional activation and nuclear targeting . Nucleic Acids Res. 23, 1184– 1191 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. LaCasse, E. & Lefebvre, Y. Nuclear localization signals overlap DNA- or RNA-binding domains in nucleic acid-binding proteins. Nucleic Acids Res. 23, 1647–1656 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kuo, C. & Leiden, J. Transcriptional regulation of T lymphocyte development and function. Annu. Rev. Immunol. 17, 149–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Ho, I., Hodge, M., Rooney, J. & Glimcher, L. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4 . Cell 85, 973–983 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Zheng, W. & Flavell, R. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression. Cell 89, 587–596 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  24. Szabo, S. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment . Cell 100, 655–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Kuo, C., Veselits, M. & Leiden, J. LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science 277, 1986–1990 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is caused by mutations of FOXP3. Nature Genet. 27, 20–21 ( 2001).

    Article  CAS  PubMed  Google Scholar 

  27. Veres, G., Gibbs, R., Scherer, S. & Caskey, C. The molecular basis of the sparse fur mouse mutation. Science 237, 415–417 (1987).

    Article  CAS  PubMed  Google Scholar 

  28. Altschul, S., Gish, W., Miller, W., Myers, E. & Lipman, D. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 ( 1990).

    Article  CAS  PubMed  Google Scholar 

  29. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Bech-Hansen, T. et al. Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness . Nature Genet. 19, 264– 267 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Strom, N.T. et al. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nature Genet. 19, 260–263 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank L. Russell for support; V. Godfrey, P. Blair and S. Witonsky for help in the initial stages of the mapping project; J. Mulligan, M. Appleby and R. Khattri for discussions; the CCH sequencing group for their diligence and efficiency; and S. Proll, M. Mortrud, D. Walker and S. Corpening for technical assistance.

Author information

Authors and Affiliations

  1. Celltech Chiroscience, Inc., Bothell, Washington, USA

    Mary E. Brunkow, Eric W. Jeffery, Kathryn A. Hjerrild, Bryan Paeper, Lisa B. Clark, Sue-Ann Yasayko & Fred Ramsdell

  2. Oak Ridge National Laboratory, Oak Ridge , Tennessee, USA

    J. Erby Wilkinson

  3. Keck Graduate Institute for Applied Life Sciences, Claremont, California, USA

    David Galas

  4. Virginia Mason Research Center, Seattle , Washington, USA

    Steven F. Ziegler

Authors
  1. Mary E. Brunkow
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Eric W. Jeffery
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Kathryn A. Hjerrild
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Bryan Paeper
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Lisa B. Clark
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Sue-Ann Yasayko
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. J. Erby Wilkinson
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. David Galas
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Steven F. Ziegler
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Fred Ramsdell
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Mary E. Brunkow.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brunkow, M., Jeffery, E., Hjerrild, K. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27, 68–73 (2001). https://doi.org/10.1038/83784

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/83784

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing