Species: mouse
Mutation name: None
type: null mutation
fertility: None
Comment: When FasL+ mouse melanoma cells were injected into FAS-deficient mutant mice, tumorigenesis was delayed. These findings led Hahne et al. (1996) to conclude that FASL may contribute to the immune privilege of tumors. They proposed further that pharmacologic products that render infiltrating T cells insensitive to FASL-induced killing may break the immunologic unresponsiveness to melanoma and provide a complementary approach in the therapy of malignant melanoma.

Species: mouse
Mutation name: None
type: null mutation
fertility: None
Comment: Hill et al.(1999) demonstrated that sunburn cell formation is dependent upon FasL. Chronic exposure to UV radiation caused 14 of 20, or 70%, of FasL-deficient mice and 1 of 20, or 5%, of wildtype mice to accumulate p53 mutations in the epidermis. Hill et al. (1999) concluded that FASL-mediated apoptosis is important for skin homeostasis, suggesting that the dysregulation of FAS-FASL interactions may be central to the development of skin cancer. FASL deficient mice were also used by Stuart et al.(1997) to demonstrate that the high percentage of successful corneal transplants, without tissue matching or immunosuppressant therapy, is related to the expression of abundant functional FASL in the cornea, capable of killing FASL(+) lymphoid cells. Using a mouse model for corneal allograft transplantation, FasL(+) orthografts were accepted at a rate of 45%, whereas FasL(-) or normal grafts transplanted to Fas(-) mice were rejected 100% of the time.

Species: human
Mutation name: None
type: naturally occurring
fertility: None
Comment: Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC self-peptide molecules, either because of incorrect thymic selection, defects in peripheral MHC class I expression, or antigen presentation. In any of these cases, failed CD8 T-cell receptor coengagement results in downregulation of genes that account for specialized cytolytic T-lymphocyte function and resistance to cell death (CD8-alpha/beta, granzyme, and LKLF), and upregulation of Fas and FasL death genes. Thus, MHC engagement is required to inhibit expression and delivery of a death program rather than to supply a putative trophic factor for T cell survival. Pestano et al. (1999) hypothesized that defects in delivery of the death signal to these cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing Fas and FasL mutations, in patients that carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients that display the cellular signature of defects in this mechanism of quality control of CD8 cells.

Species: human
Mutation name: ALPS
type: naturally occurring
fertility: None
Comment: FAS mutations in humans result in ALPS (autoimmune lymphoproliferative syndrome). Fisher et al. (1995) described 5 unrelated children with ALPS characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3(+)CD4(-)CD8(-) lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted evaluation of lymphocyte apoptosis. Each child had defective FAS-mediated T lymphocyte apoptosis associated with a unique, deleterious FAS gene mutation. One mutation appeared to cause a simple loss of function; however, 4 others had a dominant-negative phenotype when coexpressed with normal FAS. Patients have one mutated and one normal allele, ruling out a recessive mutation. From 11 families with ALPS, Vaishnaw et al.(1999) studied 8 patients to define mechanisms responsible for defective CD95-mediated apoptosis. Mutations in and around the death domain of CD95 had a dominant-negative effect explained by interference with the recruitment of the signal adaptor protein FADD to the death domain. Intracellular domain (ICD) mutations were associated with a highly penetrant Canale-Smith syndrome phenotype and an autosomal dominant inheritance pattern. In contrast, mutations affecting CD95 extracellular domain (ECD) resulted in failure of extracellular expression of mutant protein or impaired binding to CD95 ligand. These mutations did not have a dominant-negative effect. Martin et al.(1999) showed that local or global alterations in the structure of the cytoplasmic death domain from 9 independent ALPS CD95 death-domain mutations resulted in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggested that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

Species: human
Mutation name: SLE
type: None
fertility: None
Comment: FAS and FASL are candidate contributory genes in SLE, as mutations of these genes result in autoimmunity in several murine models of SLE (Kotzin et al.1997). FASL was identified in 1 SLE patient who exhibited lymphoadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained an 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion. A study of peripheral blood mononuclear cells from this patient revealed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation (Wu et al.1996).

Species: human
Mutation name: TEN
type: naturally occurring
fertility: None
Comment: Viard et al. (1998) detected high levels of soluble Fas ligand in sera of patients with toxic epidermal necrolysis (TEN). Keratinocytes of TEN patients produced FasL, which induced keratinic apoptosis. Incubating keratinocytes with intravenous immunoglobulin (IVIG) completely inhibited Fas-mediated keratinocyte apoptosis. A naturally occurring anti-Fas immunoglobulin present in IVIG blocks the Fas receptor and mediates this response.

Species: mouse
Mutation name: gld
type: naturally occurring
fertility: None
Comment: The gld (generalized lymphoproliferative disease) mutation suggests that the gld gene encodes Fas Ligand. Activated splenocytes from gld mice express Fasl mRNA. The Fas ligand protein in gld mice carried a point mutation in the C-terminal region, which is highly conserved among members of the TNF family (Takahashi et al.1994).