Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance

Genet Med. 2012 Jan;14(1):81-9. doi: 10.1038/gim.0b013e3182310b7d. Epub 2011 Oct 7.

Abstract

Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Apoptosis / genetics
  • Autoimmune Lymphoproliferative Syndrome / diagnosis
  • Autoimmune Lymphoproliferative Syndrome / genetics*
  • Cell Line
  • Fas Ligand Protein / metabolism
  • Gene Expression
  • Gene Frequency
  • Gene Order
  • Genetic Association Studies
  • Haploinsufficiency
  • Humans
  • Mutation*
  • Penetrance*
  • Protein Binding
  • Protein Structure, Tertiary / genetics
  • RNA Stability
  • T-Lymphocytes / metabolism
  • fas Receptor / chemistry
  • fas Receptor / genetics*
  • fas Receptor / metabolism

Substances

  • FAS protein, human
  • Fas Ligand Protein
  • fas Receptor