title: Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder characterized by chronic lymphoproliferation, autoimmune manifestations and expansion of TCRalphabeta+CD4-CD8- lymphocytes. The main pathogenic factor is a defective Fas-mediated apoptosis generally caused by mutations in the Fas gene. This report describes a new heterozygous Fas gene mutation in a boy with clinical and immunological features of ALPS. In vitro, T-cell blasts from the patient are completely resistant to the effects on the anti-Fas cytotoxic mAb CH-11, they also have a higher proliferation rate than T cells from healthy donors, while PHA-induced AICD is normal. The location of the mutation (I246S) found in the intracytoplasmic death domain, and the conservation of that residue in four different species from human suggest that I246 is an essential amino acid for Fas function. The patient has inherited the mutation from his father who also shows defective Fas-mediated apoptosis but the clinical and immunological manifestations are much less severe. These results provide evidence that the penetrance of genetic defects in Fas is variable and that other factors may influence the phenotype of the disease.
authors.affiliation: Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Del-Rey
authors.forename: Javier
authors.initials: J
authors.lastname: Manzanares
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Juan I
authors.initials: JI
authors.lastname: Aguiló
authors.forename: José
authors.initials: J
authors.lastname: Gómez-Rial
authors.forename: Ernesto
authors.initials: E
authors.lastname: Roldan
authors.forename: Antonio
authors.initials: A
authors.lastname: Serrano
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
authors.forename: Estela
authors.initials: E
authors.lastname: Paz-Artal
authors.forename: Luis M
authors.initials: LM
authors.lastname: Allende
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D013577:Syndrome; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor