Mutations in Fas Associated with Human Lymphoproliferative Syndrome and Autoimmunity

Abstract

Fas (also known as Apo1 and CD95) is a cell surface receptor involved in apoptotic cell death. Fas expression and function were analyzed in three children (including two siblings) with a lymphoproliferative syndrome, two of whom also had autoimmune disorders. A large deletion in the gene encoding Fas and no detectable cell surface expression characterized the most affected patient. Clinical manifestations in the two related patients were less severe: Fas-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected. These findings illustrate the crucial regulatory role of Fas and may provide a molecular basis for some autoimmune diseases in humans.

Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement

“…Losses or rearrangements of chromosomes are common in tumour cells (Popescu, 1994) Fiucci and Ruberti (1994) (RieuxLaucat et al, 1995;Cascino et al, 1996;Drappa et al, 1996) (Xerri et al, 1995). (Wu et al, 1994;Rieux-Laucat et al, 1995), suggesting that Fas signalling can control the growth of cell populations. When lpr mice, which express little Fas protein as a result of a retroviral insertion in thefas gene, are crossed with mice that overexpress the oncogene c-myc, tumour formation occurs at a greater rate than in the c-myc-expressing mice alone (Zornig et al, 1995).…”

Inactivation of the Fas gene by Alu insertion: retrotransposition in an intron causing splicing variation and autoimmune lymphoproliferative syndrome

“…2 Peripheral blood mononuclear cells (PBMC) were activated for 8 days with PHA and IL-2 (Genzyme, 20 IU/ml), then cultured with Apo-1 monoclonal ab (250 ng/ml) and a rat anti-mouse IgG (Jackson Laboratories, Westgrove, USA,10 g/ml) for 24 h. Apoptotic cells were quantified by resuspending cells in a hypotonic solution containing 0.1% sodium citrate, Genes and Immunity 0.1% Triton X-100 (Sigma, St Louis, MO, USA) and 50 g/ml propidium iodide (Sigma). Red fluorescence was measured using a FACStar plus flow cytometer (Becton Dickinson, Oxford, UK).…”

“…Mutations in the gene, located at chromosome 10p24.1 in humans, can cause lymphoproliferative disease and systemic lupus erythematosus like autoimmunity. 2,3 The majority of defects in humans are found within exons 7-9 which encode the intracellular domain of Fas, and are predominantly small deletions and mis-and nonsense mutations. Alternatively, splice site mutations may cause loss of exons.…”

Antitumor effect of allogenic fibroblasts engineered to express Fas ligand (FasL)

“…[4][5][6] Mice and humans, with a defect in Fas expression or function demonstrate a profound lymphoaccumulative disorder together with ageassociated autoimmune phenomena. [7][8][9] Mutation of FasL gene in mice resulted in similar phenotype (gld-generalized lymphoproliferative disease). 10 This suggests that the Fas/FasL system plays an important role in the maintenance of immune homeostasis.…”