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

Nature Genetics volume 27, pages 6873 (2001) | Download Citation

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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.

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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.

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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

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Correspondence to Mary E. Brunkow.

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https://doi.org/10.1038/83784

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