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

ME Brunkow, EW Jeffery, KA Hjerrild, B Paeper… - Nature …, 2001 - nature.com
ME Brunkow, EW Jeffery, KA Hjerrild, B Paeper, LB Clark, SA Yasayko, JE Wilkinson
Nature genetics, 2001nature.com
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 cytokines 1, 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 activity 3, 9. Here we identify the gene defective in sf mice by combining high …
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 cytokines 1, 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 activity 3, 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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