Journal
GENETICS IN MEDICINE
Volume 14, Issue 1, Pages 81-89Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.0b013e3182310b7d
Keywords
autoimmune lymphoproliferative syndrome; FAS; genotype-phenotype correlation; haploinsufficiency; penetrance
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Funding
- National Institutes of Health, National Human Genome Research Institute, and National Institute of Allergy and Infectious Disease, Bethesda, MD
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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.
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