title: A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype -844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup.
authors.affiliation: Servicio de Inmunología, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Del-Rey
authors.forename: Jesus
authors.initials: J
authors.lastname: Ruiz-Contreras
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Sara
authors.initials: S
authors.lastname: Calleja
authors.forename: Jose
authors.initials: J
authors.lastname: Gomez-Rial
authors.forename: Ernesto
authors.initials: E
authors.lastname: Roldan
authors.forename: Pablo
authors.initials: P
authors.lastname: Morales
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: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005091:Exons / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D006720:Homozygote; D006801:Humans; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D017354:Point Mutation / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor