title: Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance.
abstract: OBJECTIVE
  Autoimmune lymphoproliferative syndrome is a disorder of lymphocyte apoptosis. Although FAS molecules bearing mutations in the signal-transducing intracellular death domain exhibit dominant-negative interference with FAS-mediated apoptosis, mechanisms for pathology of non-death domain FAS mutations causing autoimmune lymphoproliferative syndrome are poorly defined.
  
  
  METHODS
  RNA stability, protein expression, ligand binding, and ability to transmit apoptosis signals by anti-FAS antibody or FAS ligand were determined for a cohort of 39 patients with non-death domain autoimmune lymphoproliferative syndrome. Correlations between mutation type and disease penetrance were established in mutation-positive family members.
  
  
  RESULTS
  Frameshifts or transcriptional stop mutations before exon 7 resulted in messenger RNA haploinsufficiency, whereas an amino-terminal signal sequence mutation and certain intracellular truncations prevented cell surface localization of FAS. All resulted in decreased FAS localization, inability to bind FAS ligand, and reduced FAS ligand-induced apoptosis. Extracellular missense mutations and in-frame deletions expressed defective FAS protein, failed to bind FAS ligand, and exhibited dominant-negative interference with FAS-mediated apoptosis. Mutation-positive relatives with haploinsufficient or extracellular mutations had lower penetrance of autoimmune lymphoproliferative syndrome clinical phenotypes than did relatives with death domain mutations.
  
  
  CONCLUSIONS
  We have defined molecular mechanisms by which non-death domain FAS mutations result in reduced lymphocyte apoptosis, established a hierarchy of genotype-phenotype correlation among mutation-positive relatives of patients with autoimmune lymphoproliferative syndrome, and demonstrated that FAS haploinsufficiency can lead to autoimmune lymphoproliferative syndrome.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Kennichi C
authors.initials: KC
authors.lastname: Dowdell
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Shaw
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
mesh_terms: D017209:Apoptosis / Q000235:genetics; D056735:Autoimmune Lymphoproliferative Syndrome / Q000175:diagnosis / Q000235:genetics*; D002460:Cell Line; D053222:Fas Ligand Protein / Q000378:metabolism; D015870:Gene Expression; D005787:Gene Frequency; D023061:Gene Order; D056726:Genetic Association Studies; D057895:Haploinsufficiency; D006801:Humans; D009154:Mutation; D019683:Penetrance; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D020871:RNA Stability; D013601:T-Lymphocytes / Q000378:metabolism; D019014:fas Receptor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D053222:Fas Ligand Protein; D019014:fas Receptor