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

• Published in: Genetics in medicine Vol. 14; no. 1; pp. 81 - 89
• Main Authors: Hsu, Amy P., Dowdell, Kennichi C., Davis, Joie, Niemela, Julie E., Anderson, Stacie M., Shaw, Pamela A., Rao, V. Koneti, Puck, Jennifer M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 2012; Elsevier Limited
• Subjects: Apoptosis; Apoptosis - genetics; Autoimmune Lymphoproliferative Syndrome - diagnosis; Autoimmune Lymphoproliferative Syndrome - genetics; Biomedical and Life Sciences; Biomedicine; Cell Line; Fas Ligand Protein - metabolism; fas Receptor - chemistry; fas Receptor - genetics; fas Receptor - metabolism; Gene Expression; Gene Frequency; Gene Order; Genetic Association Studies; Haploinsufficiency; Human Genetics; Humans; Laboratory Medicine; Ligands; Localization; Mutation; original-research-article; Penetrance; Protein Binding; Protein Structure, Tertiary - genetics; RNA Stability; T-Lymphocytes - metabolism; FAS; autoimmune lymphoproliferative syndrome; haploinsufficiency; genotype-phenotype correlation; penetrance
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/gim.0b013e3182310b7d

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. Genet Med 2012:14(1):81–89