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

Scurfy (sf) is an X-linked recessive mouse mutant resulting in lethality in hemizygous males 16-25 days after birth, and is characterized by overproli feration of CD4+CD8- T lymphocytes, extensive multiorgan infiltration and e levation of numerous cytokines(1-4). Similar to animals that lack expressio n of either Ctla-4 (refs, 5,6) or Tgf-beta (refs, 7,8), the pathology obser ved in sf mice seems to result from an inability to properly regulate CD4+C D8- 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 se quence analysis. The protein encoded by this gene (designated Foxp3) is a n ew member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation resul ts in a product lacking the forkhead domain. Genetic complementation demons trates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.