title: Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib.
abstract: BACKGROUND
  Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus.
  
  
  METHODS
  Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas-mediated programmed cell death.
  
  
  RESULTS
  We found an ALPS patient that harbored a heterozygous A530G mutation in the FasL gene that replaced Arg with Gly at position 156 in the protein's extracellular Fas-binding region. This produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis.
  
  
  CONCLUSIONS
  Our data explain how a naturally occurring heterozygous human FasL mutation can dominantly interfere with normal FasL apoptotic function and lead to an ALPS phenotype, designated Type Ib.
authors.affiliation: Center for Biologics Evaluation and Research, FDA, Rockville, Maryland, USA. bi@cber.fda.gov
authors.forename: Lilia L
authors.initials: LL
authors.lastname: Bi
authors.forename: George
authors.initials: G
authors.lastname: Pan
authors.forename: T Prescott
authors.initials: TP
authors.lastname: Atkinson
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Janet K
authors.initials: JK
authors.lastname: Dale
authors.forename: Christopher
authors.initials: C
authors.lastname: Makris
authors.forename: Vishnu
authors.initials: V
authors.lastname: Reddy
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Straus
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000235:genetics* / Q000276:immunology; D005260:Female; D006579:Heterozygote; D006801:Humans; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014162:Transfection
chemical_list: D053222:Fas Ligand Protein