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

Nat Genet. 2001 Jan;27(1):68-73. doi: 10.1038/83784.

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. Similar to animals that lack expression of either Ctla-4 or Tgf-beta, the pathology observed in sf mice seems to result from an inability to properly regulate CD4+CD8- T-cell activity. 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.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cloning, Molecular
  • Conserved Sequence
  • DNA Mutational Analysis
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Forkhead Transcription Factors
  • Gene Expression Profiling
  • Genes, Essential / genetics*
  • Genes, Recessive / genetics
  • Genetic Complementation Test
  • Humans
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Count
  • Lymphoproliferative Disorders / genetics*
  • Lymphoproliferative Disorders / immunology
  • Lymphoproliferative Disorders / pathology
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation / genetics*
  • Phenotype
  • Physical Chromosome Mapping
  • Protein Structure, Tertiary
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Sequence Alignment

Substances

  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • RNA, Messenger

Associated data

  • GENBANK/A49395
  • GENBANK/AF196779
  • GENBANK/AF235097
  • GENBANK/AF277991
  • GENBANK/AF277992
  • GENBANK/AF277993
  • GENBANK/AF277994
  • GENBANK/AF277995
  • GENBANK/AF277996
  • GENBANK/AF318279
  • GENBANK/AF318280
  • GENBANK/AF318281
  • GENBANK/AJ005891
  • GENBANK/U93305
  • GENBANK/X97571