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Gene Review

TNFRSF1A  -  tumor necrosis factor receptor superfamily...

Homo sapiens

Synonyms: CD120a, FPF, MS5, TBP1, TNF-R, ...
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Disease relevance of TNFRSF1A

  • TNFRSF1A mutations were found in patients of various ethnic origins, including those at risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis [1].
  • This syndrome is an autosomal dominant disorder characterized by recurring episodes of fever, arthralgia, and skin lesions that is caused by mutations in the 55-kd TNFRSF1A gene [2].
  • CONCLUSIONS: We report a novel mutation (C55S) in TNFRSF1A, resulting in autosomal-dominant periodic fever and AA amyloidosis [3].
  • Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study [4].
  • The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI [5].

Psychiatry related information on TNFRSF1A

  • Neither the polymorphism in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy [6].
  • (3) Fetuses of patients who delivered within 72 hours of cordocentesis had significantly higher concentrations of TNF-R1 and TNF-R2 receptors than those with longer latency periods (P<.05 for each) [7].
  • Measurements of the soluble TNF receptor (sTNF-R) concentrations in healthy individuals at time lapses of 3 months (17 individuals) or 1 year (51 individuals) showed a significant correlation between the first and the second measurements from each individual, implying that individual differences are stable [8].
  • The results of these studies establish a new role for myosin II motor activity in regulating TNFR-1-mediated apoptosis through the translocation of TNFR-1 to or within the plasma membrane [9].

High impact information on TNFRSF1A


Chemical compound and disease context of TNFRSF1A


Biological context of TNFRSF1A

  • Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome [18].
  • In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes [19].
  • The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers [19].
  • CONCLUSION: The C43S TNFRSF1A mutation results in decreased TNFalpha-induced nuclear signaling and apoptosis [20].
  • Comparison of these data with other published frequencies of TNFRSF1A and TNFRSF1B genotypes according to race suggests that the distribution in African American, Caucasian, and Asian populations differs significantly [21].

Anatomical context of TNFRSF1A

  • Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes [22].
  • RESULTS: Activation-induced shedding of the TNFRSF1A from neutrophils was not altered by the C43S TRAPS mutation [20].
  • TNFalpha-induced activation of NF-kappaB and AP-1 was decreased in the primary dermal fibroblasts with the C43S TNFRSF1A mutation [20].
  • Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFbeta, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability [23].
  • In some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus [24].

Associations of TNFRSF1A with chemical compounds

  • OBJECTIVE: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autoinflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor superfamily 1A (TNFRSF1A) [20].
  • RESULTS: A novel mutation, a heterozygous C to T transition in exon 3 which substitutes an isoleucine for a threonine at position 61 (T61I) was detected in the TNFRSF1A gene derived from the genomic DNA of a Japanese female TRAPS patient [25].
  • The extracellular cysteine-rich domain of the TNF-R is homologous to the nerve growth factor receptor and the B cell activation protein Bp50 [26].
  • Grb2 binds with its COOH-terminal SH3 domain to a PLAP motif within TNFR-I and with its NH2-terminal SH3 domain to SOS (son of sevenless) [27].
  • However, both TNF-R55 and TNF-R75 upregulate alpha 2 integrin expression in HUVEC [28].

Physical interactions of TNFRSF1A


Enzymatic interactions of TNFRSF1A


Regulatory relationships of TNFRSF1A


Other interactions of TNFRSF1A

  • These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades [37].
  • Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that exerts its biological functions by binding two TNF receptors (TNF-RI and TNF-RII), which initiate biological responses by interacting with adaptor and signalling proteins [38].
  • The human receptor for TRAIL was found to be an undescribed member of the TNF-receptor family (designated death receptor-4, DR4) that contains a cytoplasmic "death domain" capable of engaging the cell suicide apparatus but not the nuclear factor kappa B pathway in the system studied [39].
  • Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis [40].
  • Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFR2 as apoptotic mediators [41].

Analytical, diagnostic and therapeutic context of TNFRSF1A


  1. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Dodé, C., André, M., Bienvenu, T., Hausfater, P., Pêcheux, C., Bienvenu, J., Lecron, J.C., Reinert, P., Cattan, D., Piette, J.C., Szajnert, M.F., Delpech, M., Grateau, G. Arthritis Rheum. (2002) [Pubmed]
  2. Genetic analysis as a valuable key to diagnosis and treatment of periodic Fever. Simon, A., van Deuren, M., Tighe, P.J., van der Meer, J.W., Drenth, J.P. Arch. Intern. Med. (2001) [Pubmed]
  3. Autosomal-dominant periodic fever with AA amyloidosis: Novel mutation in tumor necrosis factor receptor 1 gene Rapid Communication. Jadoul, M., Dodé, C., Cosyns, J.P., Abramowicz, D., Georges, B., Delpech, M., Pirson, Y. Kidney Int. (2001) [Pubmed]
  4. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study. D'Hooghe, T.M., Nugent, N.P., Cuneo, S., Chai, D.C., Deer, F., Debrock, S., Kyama, C.M., Mihalyi, A., Mwenda, J.M. Biol. Reprod. (2006) [Pubmed]
  5. Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness--the ECTIM, AXA, EVA and GENIC Studies. Poirier, O., Nicaud, V., Gariépy, J., Courbon, D., Elbaz, A., Morrison, C., Kee, F., Evans, A., Arveiler, D., Ducimetière, P., Amarenco, P., Cambien, F. Eur. J. Hum. Genet. (2004) [Pubmed]
  6. Polymorphisms of the tumor necrosis factor receptors: no association with narcolepsy in German patients. Wieczorek, S., Dahmen, N., Jagiello, P., Epplen, J.T., Gencik, M. J. Mol. Med. (2003) [Pubmed]
  7. Further observations on the fetal inflammatory response syndrome: a potential homeostatic role for the soluble receptors of tumor necrosis factor alpha. Romero, R., Maymon, E., Pacora, P., Gomez, R., Mazor, M., Yoon, B.H., Berry, S.M. Am. J. Obstet. Gynecol. (2000) [Pubmed]
  8. Variation in serum levels of the soluble TNF receptors among healthy individuals. Aderka, D., Engelmann, H., Shemer-Avni, Y., Hornik, V., Galil, A., Sarov, B., Wallach, D. Lymphokine Cytokine Res. (1992) [Pubmed]
  9. Myosin ii light chain phosphorylation regulates membrane localization and apoptotic signaling of tumor necrosis factor receptor-1. Jin, Y., Atkinson, S.J., Marrs, J.A., Gallagher, P.J. J. Biol. Chem. (2001) [Pubmed]
  10. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Theill, L.E., Boyle, W.J., Penninger, J.M. Annu. Rev. Immunol. (2002) [Pubmed]
  11. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Micheau, O., Tschopp, J. Cell (2003) [Pubmed]
  12. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. McDermott, M.F., Aksentijevich, I., Galon, J., McDermott, E.M., Ogunkolade, B.W., Centola, M., Mansfield, E., Gadina, M., Karenko, L., Pettersson, T., McCarthy, J., Frucht, D.M., Aringer, M., Torosyan, Y., Teppo, A.M., Wilson, M., Karaarslan, H.M., Wan, Y., Todd, I., Wood, G., Schlimgen, R., Kumarajeewa, T.R., Cooper, S.M., Vella, J.P., Amos, C.I., Mulley, J., Quane, K.A., Molloy, M.G., Ranki, A., Powell, R.J., Hitman, G.A., O'Shea, J.J., Kastner, D.L. Cell (1999) [Pubmed]
  13. Differences in susceptibility to tumor necrosis factor alpha-induced apoptosis among MCF-7 breast cancer cell variants. Burow, M.E., Weldon, C.B., Tang, Y., Navar, G.L., Krajewski, S., Reed, J.C., Hammond, T.G., Clejan, S., Beckman, B.S. Cancer Res. (1998) [Pubmed]
  14. Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematodes, progressive systemic sclerosis, and mixed connective tissue disease. Heilig, B., Fiehn, C., Brockhaus, M., Gallati, H., Pezzutto, A., Hunstein, W. J. Clin. Immunol. (1993) [Pubmed]
  15. TNF-mediated cytotoxicity and resistance in human prostate cancer cell lines. Nakajima, Y., DelliPizzi, A.M., Mallouh, C., Ferreri, N.R. Prostate (1996) [Pubmed]
  16. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Piguet, P.F., Vesin, C. Eur. Respir. J. (1994) [Pubmed]
  17. Tumor necrosis factor receptor levels are associated with carotid atherosclerosis. Elkind, M.S., Cheng, J., Boden-Albala, B., Rundek, T., Thomas, J., Chen, H., Rabbani, L.E., Sacco, R.L. Stroke (2002) [Pubmed]
  18. Severe TNF receptor-associated periodic syndrome due to 2 TNFRSF1A mutations including a new F60V substitution. Haas, S.L., Lohse, P., Schmitt, W.H., Hildenbrand, R., Karaorman, M., Singer, M.V., Böcker, U. Gastroenterology (2006) [Pubmed]
  19. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Aksentijevich, I., Galon, J., Soares, M., Mansfield, E., Hull, K., Oh, H.H., Goldbach-Mansky, R., Dean, J., Athreya, B., Reginato, A.J., Henrickson, M., Pons-Estel, B., O'Shea, J.J., Kastner, D.L. Am. J. Hum. Genet. (2001) [Pubmed]
  20. Reduced tumor necrosis factor signaling in primary human fibroblasts containing a tumor necrosis factor receptor superfamily 1A mutant. Siebert, S., Amos, N., Fielding, C.A., Wang, E.C., Aksentijevich, I., Williams, B.D., Brennan, P. Arthritis Rheum. (2005) [Pubmed]
  21. Single-nucleotide polymorphisms in tumor necrosis factor receptor genes: definition of novel haplotypes and racial/ethnic differences. Bridges, S.L., Jenq, G., Moran, M., Kuffner, T., Whitworth, W.C., McNicholl, J. Arthritis Rheum. (2002) [Pubmed]
  22. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Aganna, E., Hammond, L., Hawkins, P.N., Aldea, A., McKee, S.A., van Amstel, H.K., Mischung, C., Kusuhara, K., Saulsbury, F.T., Lachmann, H.J., Bybee, A., McDermott, E.M., La Regina, M., Arostegui, J.I., Campistol, J.M., Worthington, S., High, K.P., Molloy, M.G., Baker, N., Bidwell, J.L., Castañer, J.L., Whiteford, M.L., Janssens-Korpola, P.L., Manna, R., Powell, R.J., Woo, P., Solis, P., Minden, K., Frenkel, J., Yagüe, J., Mirakian, R.M., Hitman, G.A., McDermott, M.F. Arthritis Rheum. (2003) [Pubmed]
  23. Relationships between fibrinolytic and inflammatory parameters in human adipose tissue: strong contribution of TNFalpha receptors to PAI-1 levels. Bastelica, D., Mavri, A., Verdierl, M., Berthet, B., Juhan-Vague, I., Alessi, M.C. Thromb. Haemost. (2002) [Pubmed]
  24. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. Masson, C., Simon, V., Hoppé, E., Insalaco, P., Cissé, I., Audran, M. Joint, bone, spine : revue du rhumatisme. (2004) [Pubmed]
  25. A novel mutation (T61I) in the gene encoding tumour necrosis factor receptor superfamily 1A (TNFRSF1A) in a Japanese patient with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) associated with systemic lupus erythematosus. Ida, H., Kawasaki, E., Miyashita, T., Tanaka, F., Kamachi, M., Izumi, Y., Huang, M., Tamai, M., Origuchi, T., Kawakami, A., Migita, K., Motomura, M., Yoshimura, T., Eguchi, K. Rheumatology (Oxford, England) (2004) [Pubmed]
  26. Molecular cloning and expression of a receptor for human tumor necrosis factor. Schall, T.J., Lewis, M., Koller, K.J., Lee, A., Rice, G.C., Wong, G.H., Gatanaga, T., Granger, G.A., Lentz, R., Raab, H. Cell (1990) [Pubmed]
  27. Identification of Grb2 as a novel binding partner of tumor necrosis factor (TNF) receptor I. Hildt, E., Oess, S. J. Exp. Med. (1999) [Pubmed]
  28. Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. Mackay, F., Loetscher, H., Stueber, D., Gehr, G., Lesslauer, W. J. Exp. Med. (1993) [Pubmed]
  29. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. Cui, X., Hawari, F., Alsaaty, S., Lawrence, M., Combs, C.A., Geng, W., Rouhani, F.N., Miskinis, D., Levine, S.J. J. Clin. Invest. (2002) [Pubmed]
  30. Interleukin-10-induced HIV-1 expression is mediated by induction of both membrane-bound tumour necrosis factor (TNF)-alpha and TNF receptor type 1 in a promonocytic cell line. Barcellini, W., Rizzardi, G.P., Marriott, J.B., Fain, C., Shattock, R.J., Meroni, P.L., Poli, G., Dalgleish, A.G. AIDS (1996) [Pubmed]
  31. A death-domain-containing receptor that mediates apoptosis. Kitson, J., Raven, T., Jiang, Y.P., Goeddel, D.V., Giles, K.M., Pun, K.T., Grinham, C.J., Brown, R., Farrow, S.N. Nature (1996) [Pubmed]
  32. Selective regulation by delta-PKC and PI 3-kinase in the assembly of the antiapoptotic TNFR-1 signaling complex in neutrophils. Kilpatrick, L.E., Sun, S., Korchak, H.M. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  33. Activation of MAP kinase-activated protein kinase 2 in human neutrophils after phorbol ester or fMLP peptide stimulation. Zu, Y.L., Ai, Y., Gilchrist, A., Labadia, M.E., Sha'afi, R.I., Huang, C.K. Blood (1996) [Pubmed]
  34. TNF-induced superoxide anion production in adherent human neutrophils involves both the p55 and p75 TNF receptor. Richter, J., Gullberg, U., Lantz, M. J. Immunol. (1995) [Pubmed]
  35. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. Srinivasula, S.M., Ahmad, M., Ottilie, S., Bullrich, F., Banks, S., Wang, Y., Fernandes-Alnemri, T., Croce, C.M., Litwack, G., Tomaselli, K.J., Armstrong, R.C., Alnemri, E.S. J. Biol. Chem. (1997) [Pubmed]
  36. Oxidative stress promotes ligand-independent and enhanced ligand-dependent tumor necrosis factor receptor signaling. Ozsoy, H.Z., Sivasubramanian, N., Wieder, E.D., Pedersen, S., Mann, D.L. J. Biol. Chem. (2008) [Pubmed]
  37. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Boldin, M.P., Goncharov, T.M., Goltsev, Y.V., Wallach, D. Cell (1996) [Pubmed]
  38. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Li, X., Yang, Y., Ashwell, J.D. Nature (2002) [Pubmed]
  39. The receptor for the cytotoxic ligand TRAIL. Pan, G., O'Rourke, K., Chinnaiyan, A.M., Gentz, R., Ebner, R., Ni, J., Dixit, V.M. Science (1997) [Pubmed]
  40. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Natoli, G., Costanzo, A., Ianni, A., Templeton, D.J., Woodgett, J.R., Balsano, C., Levrero, M. Science (1997) [Pubmed]
  41. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Pimentel-Muiños, F.X., Seed, B. Immunity (1999) [Pubmed]
  42. No association of polymorphisms in the tumor necrosis factor receptor I and receptor II genes with disease severity in rheumatoid arthritis. Glossop, J.R., Nixon, N.B., Dawes, P.T., Hassell, A.B., Mattey, D.L. J. Rheumatol. (2003) [Pubmed]
  43. Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour. Todd, I., Radford, P.M., Draper-Morgan, K.A., McIntosh, R., Bainbridge, S., Dickinson, P., Jamhawi, L., Sansaridis, M., Huggins, M.L., Tighe, P.J., Powell, R.J. Immunology (2004) [Pubmed]
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