Defective Fas Mediated Apoptosis In A Human Autoimmune Lymphoproliferative Syndrome

We recently described 5 unrelated children with autoimmune lymphoproliferative syndrome (ALPS) whom had dominant interfering mutations in Fas, a transmembrane protein of the tumor necrosis receptor family that mediates apoptosis of lymphoid cells. All 5 children with ALPS had heterozygous mutations in Fas; 4 of the mutant Fas molecules were shown to dominantly interfere with the induction of apoptosis by wild type Fas. The 5 children had massive non-mailgnant lymphadenopathy, autoimmune thrombocytopenia, hemolytic anemia, hyper-gammaglobulinemia as well as significant expansion of an unsusual subset of T cells that express T-cell receptors but neither CD4 nor CD8 (CD4-/CD8-). As seen in MRL/lpr mice, which also have autoimmune phenotype and elevated CD4-/CD8- T-cells, our patients demonstrated defective programmed cell death in response to Fas stimulation. A sixth ALPS patient has now been studied and found not to have a mutation in either allele of the Fas gene. Clinically this patient is indistinguishable from the previously characterized ALPS patients and like them has defective Fas-mediated apoptosis, in-vitro. Furthermore this patient's parents have normal Fas mediated apoptosis. The pattern of inheritance and our molecular charactreization of this ALPS patient are consistent with a recessive defect in an intracellular signalling molecule of the Fas apoptotic pathway and that both parents are carriers for this mutation.