Alternative titles; symbols
HGNC Approved Gene Symbol: FAS
Cytogenetic location: 10q23.31 Genomic coordinates (GRCh38): 10:88,964,050-89,017,059 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.31 | {Autoimmune lymphoproliferative syndrome} | 601859 | Autosomal dominant | 3 |
| Autoimmune lymphoproliferative syndrome, type IA | 601859 | Autosomal dominant | 3 | |
| Squamous cell carcinoma, burn scar-related, somatic | 3 |
Itoh et al. (1991) isolated cDNAs encoding the human FAS antigen from a human T-cell lymphoma cDNA library. Sequence analysis predicted a 16-amino acid signal sequence followed by a mature protein of 319 amino acids with a single transmembrane domain and a molecular mass of approximately 36 kD. The FAS antigen shows structural homology with a number of cell surface receptors, including tumor necrosis factor (TNF) receptors (191190, 191191) and the low-affinity nerve growth factor receptor (NGFR; 162010). Northern blot analysis detected 2.7- and 1.9-kb FAS mRNAs in thymus, liver, ovary, and heart. Functional expression studies in mouse cells showed that the FAS antigen induced antibody-triggered apoptosis.
Watanabe-Fukunaga et al. (1992) isolated mouse Fas antigen from a murine macrophage cDNA library. The deduced 306-amino acid sequence shares 49.3% sequence identity with the human sequence. Northern blot analysis detected a 2.1-kb Fas antigen mRNA in mouse thymus, heart, liver, and ovary.
Oehm et al. (1992) demonstrated that the 48-kD APO1 antigen, defined by the mouse monoclonal antibody anti-APO1, is the same as the FAS antigen. APO1 was expressed on the cell surface of various normal and malignant cells, including activated human T and B lymphocytes and a variety of malignant human lymphoid cell lines, and binding of anti-APO1 antibody to the APO1 antigen induced apoptosis.
Antisense Transcript SAF
Yan et al. (2005) described a novel RNA transcribed from the opposite strand of intron 1 of the human FAS gene, which they named SAF. The 1.5-kb transcript was expressed in human heart, placenta, liver, muscle, and pancreas, as well as in several cancer cell lines. SAF-transfected Jurkat cells were highly resistant to FAS-mediated but not to TNF-alpha (191160)-mediated apoptosis, compared to control transfectants. Although the overall mRNA expression level of FAS was not affected, expression of some novel forms of FAS transcripts was increased in SAF-transfected cells. Yan et al. (2005) hypothesized that SAF may protect T lymphocytes from FAS-mediated apoptosis by blocking the binding of FASL or its agonistic FAS antibody, and that SAF may regulate expression of FAS alternative splice forms through pre-mRNA processing.
Yan et al. (2005) noted that the TNFRSF6 gene contains 9 exons. They identified an antisense transcript SAF within the 12.1-kb intron 1 that is transcribed in the opposite direction as the TNFRSF6 gene.
Inazawa et al. (1992) mapped the human FAS gene to chromosome 10q24.1 by fluorescence in situ hybridization. Using cosmid DNA containing the FAS gene as a probe for fluorescence in situ hybridization, Lichter et al. (1992) mapped the FAS gene to a subregion of chromosomal band 10q23; the analysis showed that the FAS gene is located just distal to the central part of band 10q23.
Watanabe-Fukunaga et al. (1992) mapped the mouse Fas gene to the distal region of chromosome 19.
Talal (1994) used the term 'autogene,' a neologism, to refer to a gene whose abnormal function contributes to the development of autoimmune disease; the term is parallel to the term oncogene and the role of its product in malignancy. Mountz and Talal (1993) suggested that FAS is the first known autogene.
Dhein et al. (1995) found that T-cell receptor-induced apoptosis was mediated by an APO1 ligand and APO1 in vitro. Apoptosis was significantly reduced by inhibition of anti-APO1 antibodies. Brunner et al. (1995) showed that the Fas antigen receptor was rapidly expressed on T cells following activation of T-cell hybridomas, and that the interaction between FAS and FAS ligand (FASL, CD95L, or TNFSF6; 134638) induced cell death in a cell-autonomous manner consistent with apoptosis. Interference with the FAS/FASL interaction inhibited activation-induced apoptosis. Ju et al. (1995) also showed that the interaction between FAS and FASL results in activation-induced T-cell death.
Viard et al. (1998) detected high levels of soluble FASL in the sera of patients with toxic epidermal necrolysis (TEN; 608579). Keratinocytes of TEN patients produced FASL, which induced keratinic apoptosis. In vitro, intravenous immunoglobulin (IVIG) completely inhibited FAS-mediated keratinocyte apoptosis, and in vivo, 10 TEN patients treated with IVIG showed rapid improvement in skin disease. The authors noted that a naturally occurring anti-FAS immunoglobulin present in IVIG blocked the FAS receptor and mediated this response.
Hueber et al. (1997) demonstrated that MYC (190080)-induced apoptosis required interaction on the cell surface between CD95 and its ligand. The findings linked 2 apoptotic pathways previously thought to be independent and established the dependence of MYC on CD95 signaling for its killing activity.
Pestano et al. (1999) identified a differentiative pathway taken by CD8 cells bearing receptors that cannot engage class I MHC (see 142800) self-peptide molecules 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, see 186730; granzyme B, 123910; and LKLF, 602016), 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 aberrant T cells underlie the explosive growth and accumulation of double-negative T cells in animals bearing FAS and FASL mutations, in patients who carry inherited mutations of these genes, and in about 25% of systemic lupus erythematosus patients who display the cellular signature of defects in this mechanism of quality control of CD8 cells.
Mannick et al. (1999) demonstrated that FAS activates caspase-3 (600636) by inducing the cleavage of the caspase zymogen to its active subunits and by stimulating the denitrosylation of its active site thiol.
Hueber (2000) described the signaling pathway leading to apoptosis. FAS (CD95) crosslinking with FAS ligand (CD95L) results in the formation of a death-inducing signaling complex (DISC) composed of CD95, the signal adaptor protein FADD (602457), and procaspase-8. This association generates CASP8 (601763), activating a cascade of caspases. Lepple-Wienhues et al. (1999) showed that in addition to the role of CD95 in inducing cell death, stimulation of CD95 inhibits the influx of calcium normally induced by activation of the T-cell antigen receptor, in part by not affecting the release of calcium from intracellular stores. This block in calcium entry can be mimicked by stimulating T cells with acid sphingomyelinase metabolites of the plasma membrane lipid sphingomyelin, such as ceramide and sphingosine.
Arscott et al. (1999) examined FAS expression in thyroid tissue derived from patients with papillary carcinoma and follicular cancer. More intense immunohistologic staining for the FAS protein was observed on papillary cancer cells as compared with adjacent normal follicles. FAS expression was detected at levels up to 3-fold higher in cancerous thyrocytes compared with paired normal cells. The authors concluded that the FAS antigen is expressed and functional on papillary thyroid cancer cells and that this may have potential therapeutic significance.
Grassme et al. (2000) showed that Pseudomonas aeruginosa infection induced apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95L system. Deficiency of CD95 or CD95L on epithelial cells prevented apoptosis of lung epithelial cells in vivo as well as in vitro. The importance of CD95/CD95L-mediated lung epithelial cell apoptosis was demonstrated by the rapid development of sepsis in mice deficient in either CD95 or CD95L, but not in normal mice, after P. aeruginosa infection.
Natural inhibitors of angiogenesis are able to block pathologic neovascularization without harming the preexisting vasculature. Volpert et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I (188060) and pigment epithelium-derived factor (172860), induced FAS/FASL-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FASL on endothelial cells. Expression of FAS antigen on endothelial cells and vessels was greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FASL. The antiangiogenic activity of thrombospondin I and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of FAS and FASL and the resulting apoptosis. Volpert et al. (2002) concluded that this example of cooperation between pro- and antiangiogenic factors in the inhibition of angiogenesis provided one explanation for the ability of inhibitors to select remodeling capillaries for destruction.
Raoul et al. (2002) showed that FAS triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the FAS signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD/CASP8 pathway were needed for motor neuron cell death. No evidence for involvement of the FAS/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing amyotrophic lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed increased susceptibility to activation of the FAS/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell pathways may contribute to motor neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered expression of FASL in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low-activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS.
Using mouse primary neurons and a human neuroblastoma cell line, Desbarats et al. (2003) determined that FAS can mediate neurite growth. Activation of FAS resulted in axon regeneration in primary neurons and accelerated functional recovery after sciatic nerve injury in vivo. Desbarats et al. (2003) determined that activation triggered a nerve growth factor (162030)-independent signaling pathway that included activation of ERK (see 176872) and the expression of p35 (603460).
Zou et al. (2007) reported that the hepatocyte growth factor receptor MET (164860) plays an important part in preventing FAS-mediated apoptosis of hepatocytes by sequestering FAS. They also showed that FAS antagonism by MET is abrogated in human fatty liver disease. Through structure-function studies, the authors found that a YLGA amino acid motif located near the extracellular N terminus of the MET alpha subunit is necessary and sufficient to specifically bind the extracellular portion of FAS and to act as a potential FAS ligand (FASL; 134638) antagonist and inhibitor of FAS trimerization. Using mouse models of fatty liver disease, Zou et al. (2007) showed that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.
As summarized by Jost et al. (2009), distinct cell types differ in the mechanisms by which the 'death receptor' FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of effector caspases by FAS-induced activation of caspase-8 (601763) suffices for cell killing; in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the proapoptotic BID (601197) is essential. Jost et al. (2009) demonstrated that loss of XIAP (300079) function by gene targeting or treatment with a DIABLO (605219) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. Jost et al. (2009) concluded that their results showed that XIAP is the critical discriminator between type I and type II apoptosis signaling and suggested that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
Chen et al. (2010) demonstrated that cancer cells in general, regardless of their CD95 apoptosis sensitivity, depend on constitutive activity of CD95, stimulated by a cancer-produced CD95L (134638), for optimal growth. Consistently, loss of CD95 in mouse models of ovarian cancer and liver cancer reduces cancer incidence as well as the size of the tumors. The tumorigenic activity of CD95 is mediated by a pathway involving JNK (601158) and JUN (165160). These results demonstrated that CD95 has a growth-promoting role during tumorigenesis and indicated that efforts to inhibit its activity should be considered during cancer therapy.
Crystal Structure
FAS, FADD (602457), and caspase-8 (CASP8; 601763) form a death-inducing signaling complex (DISC) that is a pivotal trigger of apoptosis. Scott et al. (2009) successfully formed and isolated the human FAS-FADD death domain complex and reported the 2.7-angstrom crystal structure. The complex shows a tetrameric arrangement of 4 FADD death domains bound to 4 FAS death domains. Scott et al. (2009) showed that an opening of the FAS death domain exposes the FADD binding site and simultaneously generates a FAS-FAS bridge. The result is a regulatory FAS-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Scott et al. (2009) concluded that, in addition to depicting a previously unknown mode of death domain interactions, their results further uncovered a mechanism for receptor signaling solely by oligomerization and clustering events.
In 5 unrelated children with a rare autoimmune lymphoproliferative syndrome (ALPS; 601859) Fisher et al. (1995) identified a heterozygous mutation in the FAS antigen gene (134637.0001-134637.0005). The disorder was characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3(+)CD4(-)CD8(-) lymphocytes, and each child had defective FAS-mediated T-lymphocyte apoptosis in vitro. One mutation appeared to cause a simple loss of function (134637.0001); however, 4 others had a dominant-negative phenotype when coexpressed with normal FAS. One of the patients studied by Fisher et al. (1995) was included in the report by Sneller et al. (1992), delineating this disorder and pointing out its resemblance to autosomal recessive lpr/gld disease in the mouse. The lpr and gld mice bear mutated genes for CD95 and CD95 ligand, respectively.
Rieux-Laucat et al. (1995) analyzed expression of the FAS antigen and its function in 3 children with a lymphoproliferative syndrome, 2 of whom also had autoimmune disorders. The most severely affected patient had a large deletion in the FAS gene and no detectable cell surface expression. Clinical manifestations in the other 2 patients were less severe: FAS-mediated apoptosis was impaired and a deletion within the intracytoplasmic domain was detected.
Aspinall et al. (1999) identified 2 novel mutations in FAS that cause ALPS.
Holzelova et al. (2004) reported 6 children with type III ALPS, defined as having phenotypic features of ALPS, including elevated numbers of double-negative T cells and hypergammaglobulinemia, but normal FAS-mediated apoptosis of T cells in vitro. Double-negative T cells from all 6 patients showed heterozygous mutations in the FAS gene (see, e.g., 134637.0018). In 2 affected patients, FAS mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells, demonstrating somatic mosaicism. The study demonstrated that peripheral lymphocytes with a dominant somatic FAS mutation exhibit a selective advantage by resisting apoptosis, thus accumulating and becoming double-negative T cells.
Clementi et al. (2004) reported a 27-year-old man with ALPS who developed a large B-cell lymphoma. Genetic analysis identified a heterozygous mutation in the FAS gene and another in the perforin gene (PRF1; 170280). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. The authors concluded that the combined effect of the 2 mutant genes contributed to the development of ALPS and lymphoma in this patient.
Dowdell et al. (2010) found that 12 (38.7%) of 31 ALPS patients who were negative for germline FAS mutations carried heterozygous somatic FAS mutations in their double-negative T cells. All of the 12 somatic mutations resulted in known or predicted functional loss of normal FAS signaling; 10 mutations led to a premature stop codon. Patients with somatic FAS mutations were clinically similar to those with germline FAS mutations, although they had a slightly lower incidence of splenectomy and lower lymphocyte counts.
Role in Neoplasms
Using microdissection techniques to isolate tumor cells from biopsies of 21 burn scar-related squamous cell carcinomas, Lee et al. (1999) analyzed the entire FAS coding region and all of the splice sites and found somatic point mutations in 3 cases. No mutations were detected in 50 cases of conventional squamous cell carcinoma. The FAS mutations were located within the death domain (N239D; 134637.0014), ligand-binding domain (N102S; 134637.0015) and transmembrane domain (C162R; 134637.0016). Loss of heterozygosity (LOH) of the other FAS allele was demonstrated in tumors carrying the N239D and C162R mutations, and expression of FAS was confirmed in all tumors with FAS mutations. Burn scar-related squamous cell carcinomas are usually more aggressive than conventional squamous cell carcinomas, and Lee et al. (1999) suggested that somatic mutations in FAS may contribute to the development and/or progression of burn scar-related squamous cell carcinomas.
Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980) patients and 1,270 controls for 2 functional polymorphisms in the promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and -844T-C (134638.0002), respectively. Compared to noncarriers, there was an increased risk of developing lung cancer for carriers of either the FAS -1377AA or the FASL -844CC genotype; carriers of both homozygous genotypes had a more than 4-fold increased risk. Zhang et al. (2005) stated that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis.
Other Associations
The TNFRSF6 gene is situated on 10q in a region implicated in several linkage studies of Alzheimer disease (AD6; 605526). Feuk et al. (2000) found an association between early-onset nonfamilial AD and a promoter polymorphism in the TNFRSF6 gene. Feuk et al. (2003) further investigated the TNFRSF6 region in 121 patients with early-onset dementia and 152 controls. Analysis showed linkage disequilibrium clustered in 2 large blocks containing a limited number of haplotypes. Genotyping of haplotype tagging markers in an additional 204 late-onset AD cases and 177 controls showed that the previously associated marker, located in the promoter of TNFRSF6, had significant association with cognitive status in Scottish early-onset dementia samples, with the strongest signals being evident in the subgroup who carried APOE4 (see 107741). The results, together with previous data, suggested that a promoter marker in TNFRSF6 plays a moderate but demonstrable role in AD etiology.
In a study of 8 patients with ALPS caused by mutation in the CD95 gene, Vaishnaw et al. (1999) found that mutations in and around the death domain had a dominant-negative effect that was explained by interference with the recruitment of the signal adaptor protein FADD to the death domain. The intracellular domain (ICD) mutations were associated with a highly penetrant phenotype and an autosomal dominant inheritance pattern. In contrast, mutations affecting the extracellular domain (ECD) of the protein resulted in failure of extracellular expression of CD95 or impaired binding to CD95 ligand; these mutations did not have a dominant-negative effect. In each of the families with an ECD mutation, only a single individual was affected. These observations were consistent with different mechanisms of action and modes of inheritance of ICD and ECD mutations, suggesting that individuals with an ECD mutation may require additional defect(s) for expression of ALPS.
Jackson et al. (1999) found that of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7 to 9, which encode the intracellular portion of FAS. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-FAS agonist monoclonal antibody. In cotransfection experiments, FAS constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wildtype FAS; however, mutations affecting the intracellular domain resulted in more severe inhibition of apoptosis and showed a higher penetrance of the ALPS phenotype. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Jackson et al. (1999) concluded that the location of mutations within APT1 strongly influences the development and the severity of ALPS.
Martin et al. (1999) contributed to the understanding of the mechanism by which heterozygous mutations in the CD95 receptor result in dominant interference with apoptosis leading to ALPS. They 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.
Siegel et al. (2000) found that dominant interference of FAS mutations stems from ligand-independent interaction of wildtype and mutant FAS receptors through a specific region of the extracellular domain, rather than depending upon ligand-induced receptor oligomerization, This domain, located within the first cysteine-rich domain, is termed the pre-ligand assembly domain (PLAD). Siegel et al. (2000) identified preassociated FAS complexes in living cells by means of fluorescence resonance energy transfer. In a large number of ALPS patients, they found that the PLAD was preserved in every example of dominant-negative mutation. To cause dominant interference, the mutant protein must physically interact with the wildtype protein in a preassociated receptor complex which normally permits FAS signaling.
Watanabe-Fukunaga et al. (1992) noted that the murine phenotype autosomal recessive lymphoproliferation (lpr) is characterized by lymphadenopathy, hypergammaglobulinemia, multiple autoantibodies, and the accumulation of large numbers of nonmalignant CD4-, CD8- T cells. Affected mice usually develop a systemic lupus erythematosus (SLE; 152700)-like autoimmune disease. Studies suggested a defect in the negative selection of self-reactive T lymphocytes in the thymus. In lpr mice, Watanabe-Fukunaga et al. (1992) identified a 786T-A transversion in the Fas gene, resulting in an asparagine-to-isoleucine substitution in a highly conserved cytoplasmic region of the protein, demonstrating that lpr is the gene for the mouse Fas antigen. The authors noted that Frizzera et al. (1989) had identified human patients displaying a phenotype similar to that of lpr mice (see 601859).
Wu et al. (1993) observed autoimmune disease in mice due to integration of endogenous retrovirus in the Fas gene.
Savinov et al. (2003) evaluated the importance of Fas in the pathogenesis of diabetes by generating NOD mice (nonobese diabetic mice that develop spontaneous autoimmune diabetes) with beta cell-specific expression of a dominant-negative point mutation in the Fas death domain. Spontaneous diabetes was significantly delayed in these mice, and the effect depended on the expression level of the transgene. However, mice bearing the transgene were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, expression of the transgene neutralized the accelerating effect of transgenic Fas ligand expressed by the same beta cells. The authors concluded that both Fas-dependent and -independent mechanisms are involved in beta cell destruction, but interference with the Fas pathway early in disease development may retard or prevent diabetes progression.
Song et al. (2003) investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the FAS gene to protect mice from liver failure and fibrosis in 2 models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from these mice were resistant to apoptosis when exposed to Fas-specific antibody or cocultured with concanavalin-A-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before concanavalin-A challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days.
Ma et al. (2004) observed that Fas-deficient (lpr/lpr) mice had less severe collagen-induced arthritis, but higher levels of Il1b (147720) in joints, than control mice, suggesting inefficient activation through Il1r1 (147810). Fas- and Fasl-deficient mouse macrophages and human macrophages treated with an antagonistic FASL antibody had suppressed NFKB (see 164011) activation and cytokine production in response to IL1B or lipopolysaccharide. Ectopic expression of FADD or dominant-negative FADD (containing the death domain only) suppressed MYD88 (602170)-induced NFKB and IL6 (147620) promoter activation and cytokine expression. Ma et al. (2004) concluded that the FAS-FASL interaction enhances activation through the IL1R1 or TLR4 (603030) pathway, possibly contributing to the pathogenesis of chronic arthritis.
Landau et al. (2005) found that Fas-deficient lymphoproliferative mice developed a Parkinson disease (PD; 168600) phenotype, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, after treatment with the dopaminergic neurotoxin MPTP at a dose that caused no phenotype in wildtype mice. Mice with mutated Fasl and generalized lymphoproliferative disease had an intermediate phenotype. Treatment of cultured midbrain neurons with Fasl to induce Fas signaling protected them from MPTP toxicity. Mice lacking only Fas exon 9, which encodes the death domain, but retaining the intracellular Fas domain and cell surface expression of Fas, were resistant to MPTP. Peripheral blood lymphocytes from patients with idiopathic PD showed a highly significant deficit in their ability to upregulate Fas after mitogen stimulation. Landau et al. (2005) concluded that reduced FAS expression increases susceptibility to neurodegeneration and that FAS has a role in neuroprotection.
Hutcheson et al. (2008) found that patients with SLE displayed increased expression of antiapoptotic members of the BCL2 (151430) and FAS apoptotic pathways in mononuclear cells. They found that Fas lpr/lpr mice that also lacked the BCL2 proapoptotic member Bim (Bim -/-) developed severe SLE-like disease by 16 weeks of age, whereas Bim -/- or Fas lpr/lpr mice did not. Antigen-presenting cells (APCs) from Bim -/- Fas lpr/lpr double-mutant mice were markedly activated and their numbers were increased in lymphoid tissues and kidneys, though numerous apoptotic (TUNEL-positive) cells were observed in glomeruli of these mice. Hutcheson et al. (2008) concluded that dysregulation of the BCL2 or FAS pathways can alter the function of APCs and lead to SLE pathogenesis.
Weant et al. (2008) found that mice lacking both Bim and Fas showed a synergistic disruption of lymphoid homeostasis, rapid onset of autoimmunity, and organ-specific blocks on contraction of antiviral immune responses. The double-mutant mice had 100-fold more antigen-specific memory Cd8-positive T cells in their lymph nodes than did wildtype mice. Weant et al. (2008) concluded that multiple death pathways function concurrently to balance proliferation and apoptosis and to prevent autoimmunity and downsize T-cell responses.
Beautyman (1995) stated that the word 'apoptosis' was 'taken straight from Liddell and Scott's classical Greek-English lexicon complete with examples of its use in medicine by Hippocrates and Dioscorides (the physician, not the poet).' He stated, furthermore, that for this reason it should be pronounced with 2 'p's. He pointed out that Kerr et al. (1972), in introducing the term into modern science, suggested silencing the second p. Silencing the p seems so well established in words of similar derivation, such as 'ptosis' and 'pneumonia,' that silencing of the second p would seem appropriate in modern speech.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Fisher et al. (1995) identified a heterozygous 1-bp deletion (429delG) in exon 3 of the FAS gene, resulting in a frameshift and premature termination. The authors predicted reduced surface expression of the Fas antigen and a loss of function. As the patient's unaffected mother was also heterozygous for the same mutation, the authors suggested that additional modifier genes may be involved in the development of the phenotype.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Fisher et al. (1995) found in-frame deletion of exon 3 of the FAS gene, resulting from a 1-bp insertion in the 5-prime splice site of intron 3 and leading to a change in the extracellular domain of the protein. Although the patient's mother, who was heterozygous for the same mutation, had no clinical abnormalities, in vitro analysis showed impaired T-lymphocyte apoptosis. Fisher et al. (1995) concluded that the exon 3 deletion had a dominant interfering effect, but also noted that genetic modifiers must be involved.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Fisher et al. (1995) identified a heterozygous 915A-C transversion in the FAS gene, resulting in a thr225-to-pro (T225P) substitution in the death domain of the protein. The father had died of Hodgkin disease, but the paternal uncle, who also had Hodgkin disease, was heterozygous for the T225P mutation, indicating that the patient's father was the source of the mutation. The mutation resulted in a dominant interfering effect.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Fisher et al. (1995) identified an A-to-C change at the 3-prime splice site of intron 6 of the FAS gene, resulting in aberrant splicing and truncation at the intracellular side of the membrane-spanning domain. The asymptomatic mother was heterozygous for the same mutation, but appeared to be a mosaic. In vitro studies showed that the mother had defective T-lymphocyte apoptosis. The authors concluded that the mutation had a dominant interfering effect.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Fisher et al. (1995) identified a heterozygous 1011C-T transition in the FAS gene, resulting in a gln257-to-ter (Q257X) substitution in the death domain of the protein. The patient's asymptomatic mother had the same heterozygous mutation, suggesting that other genetic modifiers were involved in phenotypic expression.
Bettinardi et al. (1997) described a family in which 3 sibs affected with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859) were compound heterozygous for 2 mutations in the FAS gene: a 555C-T transition, resulting in an arg105-to-trp (R105W) substitution, was inherited from the mother, and an 889A-G transition, resulting in a tyr216-to-cys (Y216C; 134637.0007) substitution, was inherited from the father. The children shared common features, including splenomegaly and lymphadenopathy, but only 1 developed severe autoimmune hemolytic anemia and thrombocytopenia. Another child developed hypergammaglobulinemia, with increased IgG and IgA serum levels. No clinical or immunologic defect and no evidence of defective FAS function was identified in the heterozygous parents.
For discussion of the tyr216-to-cys (Y216C) mutation in the FAS gene that was found in compound heterozygous state in sibs with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859) by Bettinardi et al. (1997), see 134637.0006.
In a family with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859) containing 11 affected individuals in 4 generations, Infante et al. (1998) identified a heterozygous 973A-T transversion in the FAS cDNA, resulting in a nonconservative asp244-to-val (D244V) substitution in the intracellular domain of the protein. Although 1 affected individual died of postsplenectomy sepsis and 1 had been treated for lymphoma, the FAS mutation in this family was compatible with a healthy adulthood, as clinical features of ALPS receded with increasing age.
In affected members of a family with an autosomal dominant form of autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Vaishnaw et al. (1999) identified a heterozygous G-to-C transversion in the FAS gene, resulting in an arg234-to-pro (R234P) substitution in the intracellular domain of the protein. The family was originally reported by Rao et al. (1974).
In affected members of a family with autosomal dominant autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Vaishnaw et al. (1999) identified a heterozygous C-to-T transition in the FAS gene, resulting in a thr254-to-ile (T254I) substitution.
In affected members of a family with autosomal dominant autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Vaishnaw et al. (1999) identified a heterozygous splice site mutation in the FAS gene, resulting in a frameshift and premature termination at position 209 (ser209-to-ter; S209X).
Jackson et al. (1999) found a -1A-T variant at the FAS signal sequence cleavage site in 13% of African American TNFRSF6 alleles. The variant mediated apoptosis less well than wildtype FAS and was partially inhibitory.
In a child with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), who was born of consanguineous parents, van der Burg et al. (2000) identified a homozygous 20-nucleotide duplication in the last exon of the FAS gene, affecting the cytoplasmic signaling domain. The patient's unaffected parents and sibs were heterozygous for the mutation. The findings indicated that this phenotype was the human homolog of the FAS-null mouse, since the patient carried a homozygous mutation in the FAS gene and showed a severe and accelerated ALPS phenotype. Van der Burg et al. (2000) noted that Rieux-Laucat et al. (1995) had reported a severe case of ALPS with a homozygous FAS deletion, and that Bettinardi et al. (1997) had reported 3 sibs who were compound heterozygous for 2 FAS mutations (see 134637.0006 and 134637.0007).
In a burn scar-related squamous cell carcinoma, Lee et al. (1999) identified a 957A-G transition in the TNFRSF6 gene, resulting in an asn239-to-asp (N239D) substitution in the FAS death domain.
In a burn scar-related squamous cell carcinoma, Lee et al. (1999) identified a 547A-G transition in the TNFRSF6 gene, resulting in an asn102-to-ser (N102S) substitution in the FAS ligand-binding domain.
In a burn scar-related squamous cell carcinoma, Lee et al. (1999) identified a 726T-to-C transition in the TNFRSF6 gene, resulting in a cys162-to-arg (C162R) substitution in the FAS transmembrane domain.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Martin et al. (1999) identified a heterozygous 934G-C transversion in the TNFRSF6 gene, resulting in a gly231-to-ala (G231A) substitution. (The authors originally referred to the nucleotide transversion as 943G-C and the substitution as ARG234PRO, which they later corrected in an erratum.)
In 3 of 6 patients with heterozygous mosaic cases of autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859), Holzelova et al. (2004) identified a frameshift mutation in exon 8 of the FAS gene, resulting in a premature stop at codon 204. Clinical manifestations in the 3 mosaic cases were highly variable. The same mutation had been described as a germline mutation in a patient with ALPS1A by Rieux-Laucat et al. (1999).
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859) reported by Canale and Smith (1967), Drappa et al. (1996) identified a heterozygous 1-bp insertion within the death domain of the FAS gene, resulting in a lys230to-ter (K230X) substitution.
In a patient with autoimmune lymphoproliferative syndrome type IA (ALPS1A; 601859) reported by Canale and Smith (1967), and in his affected son, Drappa et al. (1996) identified a heterozygous 972G-T transversion within the death domain of the FAS gene, resulting in an asp244-to-tyr (D244Y) substitution.
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