tumor necrosis factor receptor superfamily,member 1A /12p13.2Previous Symbols: TNFR1
Entrez Gene: 7132
HUGO Accession: HGNC:11916
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OMIM (Online Mendellian Inheritance in Man)
Tumor necrosis factor-alpha (TNFA; 191160), a potent cytokine, elicits a broad spectrum of biologic responses which are mediated by binding to a cell surface receptor. Stauber et al. (1988) isolated the receptor for human TNF-alpha from a human histiocytic lymphoma cell line.
Hohmann et al. (1989) concluded that there are 2 different proteins that serve as major receptors for TNF-alpha, one associated with myeloid cells and one associated with epithelial cells.
Using monoclonal antibodies, Brockhaus et al. (1990) obtained evidence for 2 distinct TNF-binding proteins, both of which bind TNF-alpha and TNF-beta (TNFB; 153440) specifically and with high affinity. Gray et al. (1990) isolated the cDNA for one of the receptors. They found that it encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues in the cytoplasmic domain of 221 residues. Aggarwal et al. (1985) showed that tumor necrosis factors alpha and beta initiate their effects on cell function by binding to common cell surface receptors. The TNFA and TNFB receptors are different sizes and are expressed differentially in different cell lines (Hohmann et al., 1989; Engelmann et al., 1990). TNFAR, referred to by some as TNFR55, is the smaller of the 2 receptors. cDNAs for both receptors have been cloned and their nucleic acid sequence determined (Loetscher et al., 1990; Nophar et al., 1990; Schall et al., 1990; Smith et al., 1990). Whereas the extracellular domains of the 2 receptors are strikingly similar in structure, their intracellular domains appear to be unrelated. Southern blot analysis of human genomic DNA, using the cDNAs of the 2 receptors as probes, indicated that each is encoded by a single gene.
Preassembly or self-association of cytokine receptor dimers (e.g., IL1R, see 147810; IL2R, 147730; and EPOR, 133171) occurs via the same amino acid contacts that are critical for ligand binding. Chan et al. (2000) found that, in contrast, the p60 (TNFRSF1A) and p80 (TNFRSF1B; 191191) TNFA receptors self-assemble through a distinct functional domain in the TNFR extracellular domain, termed the pre-ligand assembly domain (PLAD), in the absence of ligand. Deletion of the PLAD results in monomeric presentation of p60 or p80. Flow cytometric analysis showed that efficient TNFA binding depends on receptor self-assembly. They also found that other members of the TNF receptor superfamily, including the extracellular domains of TRAIL (TNFRSF10A; 603611), CD40 (109535), and FAS (TNFRSF6; 134637), all self-associate but do not interact with heterologous receptors.
Using targeted deletion mutagenesis of the TNFR1 protein, Tartaglia et al. (1993) identified an approximately 80-amino acid death domain responsible for signaling cytotoxicity within the intracellular region near the C terminus.
Castellino et al. (1997) found that PIP5K2B (603261) interacts specifically with the juxtamembrane region of TNFR1 and that treatment of mammalian cells with TNF-alpha increases PIP5K2B activity. They suggested that a subset of TNF responses may result from the direct association of PIP5K2B with TNFR1 and the induction of the phosphatidylinositol pathway.
Schievella et al. (1997) showed that TNFR1 associates with the MADD protein (603584) through a death domain-death domain interaction. They suggested that MADD provides a physical link between TNFR1 and the induction of mitogen-activated protein (MAP) kinase (e.g., ERK2; 176948) activation and arachidonic acid release.
Micheau and Tschopp (2003) reported that TNFR1-induced apoptosis involves 2 sequential signaling complexes. Complex I, the initial plasma membrane-bound complex, consists of TNFR1, the adaptor TRADD (603500), the kinase RIP1 (603453), and TRAF2 (601895) and rapidly signals activation of NF-kappa-B (see 164011). In a second step, TRADD and RIP1 associate with FADD (602457) and caspase-8 (601763), forming a cytoplasmic complex, complex II. When NF-kappa-B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP-L (603599) and the cell survives. Thus, TNFR1-mediated signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I and NF-kappa-B) fails to be activated.
Yazdanpanah et al. (2009) identified riboflavin kinase (RFK, formerly known as flavokinase; 613010) as a TNFR1-binding protein that physically and functionally couples TNFR1 to NADPH oxidase (300225). In mouse and human cells, RFK binds to both the TNFR1 death domain and to p22(phox) (608508), the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but not for Toll-like receptor (see 601194)-induced reactive oxygen species (ROS) production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. Yazdanpanah et al. (2009) concluded that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.
Tang et al. (2011) reported that PGRN (138945) bound directly to tumor necrosis factor receptors (TNFR1 and TNFR2) and disturbed the TNFA-TNFR interaction. Pgrn-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFA-activated intracellular signaling. Tang et al. (2011) concluded that PGRN is a ligand of TNFR, an antagonist of TNFA signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice.
Fuchs et al. (1992) demonstrated that the coding region and the 3-prime untranslated region of TNFR1 are distributed over 10 exons.
By Southern blot analysis of human/Chinese hamster somatic cell hybrid DNA, Milatovich et al. (1991, 1991) mapped the TNFR1 gene to 12pter-cen. Derre et al. (1991) found by nonradioactive in situ hybridization that the type 1 receptor (the p55 TNF receptor) is encoded by a gene located on chromosome 12p13.2. By in situ hybridization and Southern blot analysis of human/mouse hybrid cell lines, Baker et al. (1991) confirmed the assignment of TNFR1 to 12p13. By PCR analysis of human-mouse somatic cell hybrids and by in situ hybridization using biotinylated genomic TNFR1 DNA, Fuchs et al. (1992) localized the TNFR1 gene to 12p13. The homologous murine gene is located on mouse chromosome 6.
- Autosomal Dominant Periodic Fever Syndrome
Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In affected individuals from 7 families with TNF receptor-associated periodic fever syndrome (TRAPS; 142680), McDermott et al. (1999) found 6 different heterozygous missense mutations in the 55-kD TNF receptor gene, 5 of which disrupted conserved extracellular disulfide bonds (191190.0001-191190.0006). Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation (191190.0004) showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. McDermott et al. (1999) proposed that the autoinflammatory phenotype resulted from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptors. These results established an important class of mutations in TNF receptors. A detailed analysis of 1 such mutation suggested impaired cytokine receptor clearance as a novel mechanism of disease.
Five of the 6 missense mutations described by McDermott et al. (1999) involved cysteines participating in disulfide bonds in the first and second extracellular TNFR1 domains, while the sixth substituted a methionine for a highly conserved threonine adjacent to a cysteine involved in disulfide bonding. In considering mechanisms by which these mutations might induce inflammation, the authors evaluated several possibilities, including (1) increased affinity of mutant TNFR1 for ligand; (2) constitutive activation, possibly through the formation of intermolecular disulfide bonds between unpaired cysteines in mutant receptors; and (3) resistance of mutant TNFR1 to the normal homeostatic effects of activation-induced cleavage. Analysis of leukocytes from the 3 affected members of a family with a C52F mutation favored the third possibility.
The families studied by McDermott et al. (1999) included the most thoroughly characterized pedigree, a large Irish/Scottish family with a periodic inflammatory condition that had been termed familial Hibernian fever. In addition to the difference in mode of inheritance, a number of clinical features distinguish the disorder from familial Mediterranean fever (249100), including longer average duration of attacks, presence of conjunctivitis and periorbital edema, the distribution of cutaneous involvement, and less pronounced response to colchicine prophylaxis. The disease locus was mapped to 12p, which led to the identification of a number of plausible positional candidate genes, including the TNFR1 gene.
Among 150 patients with unexplained periodic fevers, Aksentijevich et al. (2001) identified 4 novel TNFRSF1A mutations, including cys33 to gly (C33G; 191190.0009); 1 mutation, cys30 to ser (C30S; 191190.0008), described by Dode et al. (2000); and 2 substitutions (P46L and R92Q) in approximately 1% of control chromosomes. The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, showed that these may be low-penetrance mutations rather than benign polymorphisms. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TNF receptor-associated periodic syndrome and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations. In 2 families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, Aksentijevich et al. (2001) identified no TNFRSF1A mutation, suggesting further genetic heterogeneity of the periodic fever syndromes.
Aganna et al. (2003) screened affected members of 18 families in which multiple members had symptoms compatible with TRAPS and 176 subjects with sporadic (nonfamilial) 'TRAPS-like' symptoms for mutations in the TNFRSF1A gene. They identified 3 previously reported and 8 novel mutations, including a 3-bp deletion (191190.0010) in a northern Irish family and a cys70-to-ser substitution (C70S; 191190.0011) in a Japanese family. Only 3 of the patients with sporadic TRAPS-like symptoms were found to have TNFRSF1A mutations. The authors noted that 3 members of the 'prototype familial Hibernian fever' family did not possess the C33Y mutation present in 9 other affected members. In addition, they found TNFRSF1A shedding defects and low soluble TNFRSF1A levels in both patients with TRAPS and those with sporadic TRAPS-like symptoms who did not have a mutation in the TNFRSF1A gene. Aganna et al. (2003) concluded that the genetic basis among patients with TRAPS-like features is heterogeneous and that TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.
- Other Disease Associations
Poirier et al. (2004) screened the TNFRSF1A gene for polymorphisms in 95 subjects with premature myocardial infarction (MI) who also had 1 parent who had had an MI. All 10 polymorphisms identified were genotyped in a large case-control study of patients with MI; one, arg92 to gln (R92Q), which was the only nonsynonymous polymorphism, was associated with MI (OR, 2.15; 95% CI, 1.09-4.23). Poirier et al. (2004) analyzed the distribution of the R92Q genotype in 3 other large studies in which phenotypes associated with atherosclerosis had been investigated. The R92Q polymorphism was associated with the presence of carotid plaques in 1 study, and with increased carotid intima-medial thickness in that and another study; however, no association was found between R92Q and ischemic stroke in the third study. Poirier et al. (2004) concluded that the 92Q allele may predispose to atherosclerosis and its coronary artery complications.
In Caucasian populations, the P46L mutation in TNFRSF1A, which is caused by a 224C-T transition, is considered as a low-penetrance mutation because its allele frequency is similar in patients and controls (approximately 1%). Tchernitchko et al. (2005) found an unexpected high P46L allele frequency (approximately 10%) in 2 groups from West Africa--a group of 145 patients with sickle cell anemia (603903) and a group of 349 healthy controls. These data suggested that the P46L variant is a polymorphism rather than a TRAPS causative mutation. Tchernitchko et al. (2005) proposed that the high frequency of P46L in West African populations could be explained by some biologic advantage conferred to carriers.
By sequencing the promoter regions 500 bp upstream from the transcriptional start site of members of the TNF and TNFR superfamilies, Kim et al. (2005) identified 23 novel regulatory SNPs in Korean donors. Sequence analysis suggested that 9 of the SNPs altered putative transcription factor binding sites. Analysis of SNP databases suggested that the SNP allele frequencies were similar to those for Japanese subjects but distinct from those of Caucasian or African populations.
As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for tuberculosis (TB) susceptibility in a Ugandan population (see 607948), Stein et al. (2007) studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10 (124092), IFNGR1 (107470), and TNFR1 genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection.
For a discussion of a possible association between variation in the TNFRSF1A gene and susceptibility to multiple sclerosis, see MS (126200).
Kumpfel et al. (2008) identified 20 patients with multiple sclerosis who carried a heterozygous R92Q variant in the TNFRSF1A gene and had clinical features consistent with late-onset of TRAPS, including myalgias, arthralgias, headache, fatigue, and skin rashes. Most of these patients experienced severe side effects during immunomodulatory therapy for MS. The findings suggested that the variants in the TNFRSF1A gene may play a modifying role in MS. Kumpfel et al. (2008) concluded that patients with coexistence of MS and features of TRAPS should be carefully observed during treatment.
To investigate the role of TNFR1 in beneficial and detrimental activities of TNF, Rothe et al. (1993) generated TNFR1-deficient mice by gene targeting. They found that mice homozygous for a disrupted Tnfr1 allele were resistant to the lethal effect of low doses of lipopolysaccharide after sensitization with D-galactosamine, but remained sensitive to high doses of lipopolysaccharide. An increased susceptibility of the homozygous mutant mice to infection with the facultative intracellular bacterium Listeria monocytogenes indicated an essential role of TNF in nonspecific immunity.
Flynn et al. (1995) found that mice lacking the Tnf receptor p55 gene and infected intravenously with Mycobacterium tuberculosis showed significantly decreased survival, higher bacterial loads, increased necrosis, delayed reactive nitrogen intermediate production and Inos (NOS2A; 163730) expression, and reduced protection after BCG vaccination than wildtype mice. Based on these results and studies using a monoclonal antibody to neutralize Tnf in mice, Flynn et al. (1995) concluded that Tnf and Tnf receptor p55 are necessary, if not solely responsible, for protection against murine TB infection.
Bruce et al. (1996) used targeted gene disruption to generate mice lacking either p55 or p75 TNF receptors; mice lacking both p55 and p75 were generated from crosses of the singly deficient mice. The TNFR-deficient (TNFR-KO) mice exhibited no overt phenotype under unchallenged conditions. Bruce et al. (1996) reported that damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in the TNFR-KO mice, indicating that TNF serves a neuroprotective function. Their studies indicated that TNF protects neurons by stimulating antioxidative pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice. They concluded that drugs which target TNF signaling pathways may prove beneficial in treating stroke or traumatic brain injury.
Qian et al. (2000) studied the effect of topical soluble TNFR1 on survival of murine orthotopic corneal transplants and on ocular chemokine gene expression after corneal transplantation. Topical treatment with soluble TNFR1 promoted the acceptance of allogeneic corneal transplants and inhibited gene expression of 2 chemokines associated with corneal graft rejection: RANTES (187011) and macrophage inflammatory protein 1-beta (182284). The authors concluded that topical anticytokine treatment is a feasible means of reducing corneal allograft rejection without resorting to the use of potentially toxic immunosuppressive drugs.
Zhang et al. (2004) found that the skin of Rela (164014)-deficient mice showed hyperproliferation that was reversed in Tnfr1-Rela double-knockout mice. They concluded that RELA antagonizes TNFR1-JNK (601158) proliferative signals in epidermis.
Vielhauer et al. (2005) studied immune complex-mediated glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and renal pathology were initially milder in Tnfr1-deficient mice, but at later time points were similar to those in wildtype controls, with excessive renal T-cell accumulation and reduced T-cell apoptosis. In contrast, Tnfr2-deficient mice were completely protected from glomerulonephritis at all time points, despite an intact immune system response. Tnfr2 expression on intrinsic renal cells, but not leukocytes, was essential for glomerulonephritis and glomerular complement deposition. Vielhauer et al. (2005) concluded that the proinflammatory and immunosuppressive properties of TNF segregate at the level of its receptors, with TNFR1 promoting systemic immune responses and renal T-cell death and intrinsic renal cell TNFR2 playing a critical role in complement-dependent tissue injury.
Wheeler et al. (2006) found that Tnfr1 -/- mice with experimental autoimmune encephalomyelitis (EAE) had more Ifng (147570)-secreting T cells in the central nervous system than wildtype mice, and EAE symptoms were milder with delayed onset. Antigen-presenting cells (APCs) in Tnfr1 -/- mice displayed greater expression of Il12p40 (IL12B; 161561) than those in wildtype mice. In vitro, Tnfr1 -/- APCs induced greater expression of Ifng, but not Il17 (IL17A; 603149), when cultured with primed T cells than did wildtype APCs. Wheeler et al. (2006) concluded that EAE in mice lacking Tnfr1 is attenuated in spite of increased Ifng levels, suggesting that Ifng levels do not necessarily correlate with EAE severity.
HPRD (Human Protein Reference Database)
Proteins Linked to TNFRSF1A Gene: 43