title: Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder.
abstract: Fas is an apoptosis-signaling receptor important for homeostasis of the immune system. In this study, Fas-mediated apoptosis and Fas mutations were analyzed in three Japanese children from two families with a lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia and an increase in TCR alphabeta+ CD4- CD8- T cells. Apoptosis induced by anti-Fas mAb was defective in both activated T cells and B cells, and granulocytes from these patients. Truncated Fas receptor lacking the cytoplasmic death domain caused by a point mutation in the splice region of intron 7 were demonstrated in two siblings. A homozygous point mutation in the splice acceptor of intron 3 was found in the Fas gene of the third patient, which resulted in the skipping of exon 4 and complete loss of Fas expression. Corresponding to these mutations, soluble Fas concentrations were decreased and reciprocally soluble Fas ligands were increased in patients' sera. Interestingly, co-stimulation by immobilized anti-Fas mAb in T cells from the two siblings was comparable to that seen in normal T cells. These results suggest that Fas-mediated apoptosis plays a pivotal role in immunological homeostasis in vivo, especially regarding clonal deletion of immune cells in humans.
authors.affiliation: Department of Pediatrics, School of Medicine, Kanazawa University, Ishikawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kasahara
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: Y
authors.initials: Y
authors.lastname: Niida
authors.forename: A
authors.initials: A
authors.lastname: Yachie
authors.forename: H
authors.initials: H
authors.lastname: Seki
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.forename: F
authors.initials: F
authors.lastname: Koizumi
authors.forename: S
authors.initials: S
authors.lastname: Koizumi
authors.forename: T
authors.initials: T
authors.lastname: Miyawaki
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D017209:Apoptosis; D002675:Child, Preschool; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood; D009154:Mutation; D019014:fas Receptor / Q000235:genetics*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor