Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease

The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial and multigenetic. The apoptosis genes, fas and fas ligand (fast), are candidate contributory genes in human SLE, as mutations of these genes result in autoimmunity in several murine models of this disease. In humans, fas mutations result in a familial autoimmune lymphoproliferative syndrome, but defects in Fast have not yet been identified. In this study, DNA from 75 patients with SLE was screened by single-stranded conformational polymorphism analysis for potential mutations of the extracellular domain of Fast. A heterozygous single-stranded conformational polymorphism for Fast was identified in one SLE patient, who exhibited lymphadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained an 84-bp deletion within exon 4 of the fast gene, resulting in a predicted 28 amino acid in-frame deletion. Analysis of PBMC from this patient revealed decreased Fast activity, decreased activation-induced cell death, and increased T cell proliferation after activation. This is the first report of defective Fast-mediated apoptosis related to a mutation of the human Fast gene in a patient with SLE and suggests that fast mutations are an uncommon cause of the disease.