title: A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome.
abstract: We report a novel type of mutation in the death ligand FasL that was associated with a severe phenotype of the autoimmune lymphoproliferative syndrome in two patients. A frameshift mutation in the intracellular domain led to complete loss of FasL expression. Cell death signaling via its receptor and reverse signaling via its intracellular domain were completely abrogated. In vitro lymphocyte proliferation induced by weak T cell receptor stimulation could be blocked and cell death was induced by engagement of FasL in T cells derived from healthy individuals and a heterozygous carrier, but not in FasL-deficient patient derived cells. Expression of genes implicated in lymphocyte proliferation and activation (CCND1, NFATc1, NF-κB1) was increased in FasL-deficient T cells and could not be downregulated by FasL engagement as in healthy cells. Our data thus suggest, that deficiency in FasL reverse signaling may contribute to the clinical lymphoproliferative phenotype of ALPS.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Schafiq
authors.initials: S
authors.lastname: Nabhani
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hönscheid
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Prasad T
authors.initials: PT
authors.lastname: Oommen
authors.affiliation: Department of Clinical and Molecular Virology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleckenstein
authors.affiliation: Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaper
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhlen
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Laws
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: ute.fischer@med.uni-duesseldorf.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
mesh_terms: D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D053218:Receptors, Death Domain / Q000378:metabolism*; D035781:Siblings; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D053218:Receptors, Death Domain
keywords: Autoimmune lymphoproliferative syndrome; Fas ligand; FasL reverse signaling