title: Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation.
abstract: BACKGROUND
  Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphoproliferation, accumulation of double-negative T cells, hypergammaglobulinemia G and A, and autoimmune cytopenia.
  
  
  OBJECTIVE
  Although mostly associated with FAS mutations, different genetic defects leading to impaired apoptosis have been described in patients with ALPS, including the FAS ligand gene (FASLG) in rare cases. Here we report on the first case of complete FAS ligand deficiency caused by a homozygous null mutant.
  
  
  METHODS
  Double-negative T-cell counts and plasma IL-10 and FAS ligand concentrations were determined as ALPS markers. The FASLG gene was sequenced, and its expression was analyzed by means of Western blotting. FAS ligand function was assessed based on reactivation-induced cell death.
  
  
  RESULTS
  We describe a patient born to consanguineous parents who presented with a severe form of ALPS caused by FASLG deficiency. Although the clinical presentation was compatible with a homozygous FAS mutation, FAS-induced apoptosis was normal, and plasma FAS ligand levels were not detectable. This patient carries a homozygous, germline, single-base-pair deletion in FASLG exon 1, leading to a premature stop codon (F87fs x95) and a complete defect in FASLG expression. The healthy parents were each heterozygous for the mutation, confirming its recessive trait.
  
  
  CONCLUSIONS
  FAS ligand deficiency should be screened in patients presenting with ALPS features but lacking the usual markers, including plasma soluble FAS ligand and an in vitro apoptotic defect. An activation-induced cell death test could help in discrimination.
authors.affiliation: Unité INSERM 768, Hôpital Necker-Enfants Malades, Paris, France. aude.magerus@inserm.fr
authors.forename: Aude
authors.initials: A
authors.lastname: Magerus-Chatinet
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Stolzenberg
authors.forename: Nina
authors.initials: N
authors.lastname: Lanzarotti
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Cécile
authors.initials: C
authors.lastname: Daussy
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neveux
authors.forename: Mukesh
authors.initials: M
authors.lastname: Desai
authors.forename: Meghana
authors.initials: M
authors.lastname: Rao
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
authors.forename: Manisha
authors.initials: M
authors.lastname: Madkaikar
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
mesh_terms: D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000276:immunology; D053222:Fas Ligand Protein / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein