Tumor Necrosis Factor Receptor Superfamily, Member 6

Alternative Names

  • TNFRSF6
  • Apoptosis Antigen 1
  • APT1
  • FAS Antigen
  • Surface Antigen APO1
  • APO1
  • CD95

Associated Diseases

Systemic Lupus Erythematosus
Back to search Result
OMIM Number

134637

Gene Map Locus
10q24.1

Description

The FAS receptor/CD95 is one of the best characterized members of the Tumor Necrosis Factor (TNF) receptor superfamily of proteins. The protein is known for its function in cellular apoptosis. Both membrane bound and soluble forms of the FAS receptor are seen, although only the membrane bound form is able to effect downstream signal transduction leading to apoptosis. FAS receptors exist in a homo-trimeric form, formed by the association of three FAS molecules via their N-terminal domains. Once the FAS ligand binds to this trimeric complex, Death Domains (DD) on the FAS receptors aggregate with each other and with the DD on another adaptor protein called FADD and caspase-8, forming a Death Inducing Signalling Complex (DISC). The RISC formation, in turn, initiates the subsequent cascade of caspases, mediating apoptosis.

On the other hand, the soluble form of the receptor (sFAS) has been shown to associate with the soluble FAS ligand, and consequently be internalized into the endosomal pathway of the cells. This mechanism may be important in the evasion of apoptosis by some tumor cells. Additionally, the FAS receptor may also be involved in the stimulation of T cells.

Mutations in the FAS receptor gene lead to defects in the apoptotic process, disturbing normal tissue homeostasis and function. Disease conditions known to be caused due to mutations in this gene include the Autoimmune Lymphoproliferative Syndrome (ALPS) and the rare Canala-Smith Syndrome.

Molecular Genetics

The FAS receptor gene is located on chromosome 10, where it spans a length of approximately 26 Kb, and is made up of nine exons. The FAS receptor is a typical single pass type I membrane protein, consisting of 355 amino acids, and weighing about 37 KDa. At least six isoforms of this protein are known, five of which are of the secreted form. Similar to all other death receptors, the FAS receptor contains an 80 amino acid death domain in its cytoplasmic tail, which is involved in the binding of FADD.

Epidemiology in the Arab World

View Map

Other Reports

Egypt

El-Kowrany et al. (2001) showed a significant increase in interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and soluble Fas in cutaneous leishmanial lesions as well as serum samples from infected individuals; hence, confirming the role of Fas system as an inducer of apoptosis. Similarly, Salama et al. (2003) realized that serum levels of sFas were significantly higher in 15 male patients with schistosomal cor pulmonale (74 +/- 80 U/ml) than in 15 male patients with cor pulmonale due to COPD (15 +/- 10 U/ml) and 20 normal malesubjects (19 +/- 11 U/ml, p < 0.001 in both). Additionally, serum sFas levels were in direct correlation to the severity of pulmonary hypertension, thus, suggesting an apoptotic role in schistosomal cor pulmonale as well. In 2004, Aref et al. indicated that Fas expression was significantly higher in a group of 25 patients with hepatosplenic (HS) schistosomiasis as compared to both HI and normal healthy controls (P < 0.05). Serum Fas ligand levels were significantly higher among a group of 10 patients with hepatointestinal (HI) schistosomiasis and 10 control subjects (P < 0.01 for both). Aref et al. (2004) suggested that enhanced neutrophil apoptosis demonstrated in HS patients is triggered by soluble Fas ligand, which is mostly derived from spleen.

El Sherif et al. (2005) also noted significantly higher serum sIL-2R, TNF-alpha and sFas levels in 45 patients with congestive heart failure than in a control group of 18 individuals. A significant positive correlations were found between sFas and both TNF-alpha and sIL-2R and between TNF-alpha and both nitric oxide and diastolic function. Likewise, Twfeek and Zaki (2005) showed significant increase of both TNFalpha and CD95 levels in 70 children with various renal diseases in comparison with a control group of 10 children (P<0.001). Similarly, El-Hodhod et al. (2006) also indicated that serum levels of s.Fas and Bcl-2 were significantly higher in in a group of 30 children and adolescents with idiopathic epilepsy than in 15 clinically healthy control subjects. Levels of s.Fas correlated positively with seizure severity and negatively with the duration from the last attack.

Oman

Al-Maini et al. (2000) studied whether the soluble form of the FAS apoptosis antigen (sFas) had a role in the disease activity or organ damage in SLE by measuring the sFas levels (by double antibody ELISA) of 39 Arab patients with SLE (male: female ratio of 2:37) with different degrees of disease activity and organ damage over a four year period and comparing them to those of 22 race-, gender-, and age-matched healthy individuals. Patients were subdivided into group A (total cohort), group B (patients without major organ involvement), and group C (with major organ involvement) which was further subdivided into group D (renal involvement with other major organ involvement), group E (only renal involvement), group F (central nervous system involvement with other major organ involvement), and group G (only central nervous system involvement). Results indicated that the level of sFas was higher among patients (0.60 ng/ml SD 0.38) than controls (0.26 ng/ml SD 0.11), and it was higher in all subgroups of group C (except groups F and G) than in group B. When the sFas levels was compared with organ damage index (SLICC/ACR), a positive correlation was found for the total cohort and group C but not group B. No correlation was found between sFas levels and either SLEADI or acute phase reactants. In the cohort and group C, correlation was found between sFas levels and renal function tests, liver function tests, lymphocyte and neutrophil granulocyte counts and anti Sm antibodies. No such correlation was found in group B and no significant difference of sFas levels among different drug treatment subgroups was found. Al-Maini et al. (2000) concluded that elevated serum levels of sFas could be associated with kidney or liver damage in SLE patients, although their study did not prove a causative connection. Al-Maini et al. (2000) suggested that sFas may actually prevent further damage by inhibiting Fas-mediated apoptosis; hence, could have a therapeutic role in SLE or other conditions with organ damage.

© CAGS 2024. All rights reserved.