title: Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.
abstract: Five unrelated children are described with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3+CD4-CD8- lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted an evaluation of lymphocyte apoptosis. Each child had defective Fas-mediated T lymphocyte apoptosis associated with a unique, deleterious Fas gene mutation. One mutation appeared to cause a simple loss of function; however, four others had a dominant negative phenotype when coexpressed with normal Fas. Family studies demonstrated the inheritance of the mutant Fas alleles. The occurrence of Fas mutations together with abnormal T cell apoptosis in ALPS patients suggests an involvement of Fas in this recently recognized disorder of lymphocyte homeostasis and peripheral self-tolerance.
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-4470, USA.
authors.forename: G H
authors.initials: GH
authors.lastname: Fisher
authors.forename: F J
authors.initials: FJ
authors.lastname: Rosenberg
authors.forename: S E
authors.initials: SE
authors.lastname: Straus
authors.forename: J K
authors.initials: JK
authors.lastname: Dale
authors.forename: L A
authors.initials: LA
authors.lastname: Middleton
authors.forename: A Y
authors.initials: AY
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Strober
authors.forename: M J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: J M
authors.initials: JM
authors.lastname: Puck
mesh_terms: D000954:Antigens, Surface / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019014:fas Receptor
chemical_list: D000954:Antigens, Surface; D017931:DNA Primers; D018076:DNA, Complementary; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor