Nature Genetics
27, 68 - 73 (2001)
doi:10.1038/83784
Disruption of a new forkhead/winged-helix protein, scurfin, results in
the fatal lymphoproliferative disorder of the scurfy mouseMary E. Brunkow1, Eric W. Jeffery1, Kathryn A. Hjerrild1, Bryan Paeper1, Lisa B. Clark1, Sue-Ann Yasayko1, J. Erby Wilkinson2, David Galas3, Steven F. Ziegler4
& Fred Ramsdell11
Celltech Chiroscience, Inc., Bothell,
Washington, USA. 2
Oak Ridge National Laboratory, Oak Ridge
, Tennessee, USA. 3
Keck Graduate Institute for Applied Life Sciences,
Claremont, California, USA. 4
Virginia Mason Research Center, Seattle
, Washington, USA.
Correspondence should be addressed to Mary E. Brunkow marybrunkow@chiroscience.comScurfy (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- (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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