Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and the scurfy mutant mouse

Abstract

IPEX is a rare X-linked syndrome characterized by neonatal infantile insulin dependent diabetes mellitus, enteropathy, endocrinopathy, eczema and severe infections with variable immune dysfunction. Scurfy, an X-linked lethal disorder of immune regulation, is the murine equivalent of IPEX, providing a model for the human disease. The gene responsible for scurfy has recently been identified by positional cloning. The scurfy/IPEX gene is a member of a family of transcriptional regulators that have in common a forkhead winged-helix DNA binding domain. The cloning of the human ortholog of the mouse gene confirmed that FOXP3 codes for the immune specific DNA binding protein responsible for IPEX. Missense and nonsense mutations, microdeletions, elimination of the downstream stop codon and mutations of the polyadenylation signal have been identified in affected members of families with classic IPEX. It has been suggested that FOXP3 acts as a trascriptional repressor in vivo. Treatment with Cyclosporin A or FK506 improves the clinical course and HLA identical bone marrow transplantation appears to provide a permanent cure.