Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF1A
SNOMEDCT: 403833009;
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,328,771-6,342,076 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | {Multiple sclerosis, susceptibility to, 5} | 614810 | 3 | |
| Periodic fever, familial | 142680 | Autosomal dominant | 3 |
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.
In their review, Faustman and Davis (2010) noted that there are marked differences in expression of TNFR1 and TNFR2 (TNFRSF1B; 191191). TNFR1 shows near ubiquitous expression, whereas TNFR2 is restricted to certain T-cell populations, endothelial cells, microglia and specific neuron subtypes, oligodendrocytes, cardiac myocytes, thymocytes, and mesenchymal stem cells. Thus, all cells expressing TNFR2 also express TNFR1. Erythrocytes do not express either receptor.
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) 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 receptor-1 (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.
Braumuller et al. (2013) showed that the combined action of the T helper-1-cell cytokines IFN-gamma (IFNG; 147570) and tumor necrosis factor (TNF; 191160) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumor immunity from oncogene-induced senescence, Braumuller et al. (2013) used a mouse model in which the Simian virus-40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumors by attenuating p53 (191170)- and Rb (614041)-mediated cell cycle control. When combined, Ifng and Tnf drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream Rb hypophosphorylation at ser795. This cytokine-induced senescence strictly requires Stat1 (600555) and Tnfr1 signaling in addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells permanently arrest Tag-expressing cancers by inducing Ifng- and Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as IFNG and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
Li et al. (2013) discovered that death domains in several proteins, including TRADD, FADD, RIPK1, and TNFR1, were directly inactivated by NleB, an enteropathogenic E. coli type III secretion system effector known to inhibit host NF-kappa-B signaling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signaling in enteropathogenic E. coli infected cells, including NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered NleB also blocked FAS ligand (134638) and TRAIL (603598)-induced cell death by preventing formation of a FADD-mediated death-inducing signaling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of enteropathogenic E. coli infection.
Pearson et al. (2013) reported that the type III secretion system (T3SS) effector NleB1 from enteropathogenic E. coli binds to host cell death-domain-containing proteins and thereby inhibits death receptor signaling. Protein interaction studies identified FADD, TRADD, and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical DISC and proteolytic activation of caspase-8 (601763), an essential step in death receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified arg117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defense was demonstrated using mice deficient in the FAS signaling pathway, which showed delayed clearance of the enteropathogenic E. coli-like mouse pathogen Citrobacter rodentium and reversion to virulence of an NleB mutant. Pearson et al. (2013) concluded that the activity of NleB suggested that enteropathogenic E. coli and other attaching and effacing pathogens antagonize death receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.
Kumari et al. (2013) generated apparently normal mice lacking both Ikk2 (IKBKB; 603258) and Tnfr1 specifically in keratinocytes. However, Ikk2 -/- mice expressing Tnfr1 exclusively on epidermal keratinocytes developed skin inflammation. The authors detected increased Tnfr1-dependent Il24 (604136) expression and activation of Stat3 (102582) signaling in keratinocytes of mice that developed psoriasis-like skin inflammation. RT-PCR analysis showed that IL24 was also strongly expressed in human psoriatic epidermis. Pharmacologic inhibition of NFKB in TNF-stimulated primary human keratinocytes also increased IL24 expression. Kumari et al. (2013) proposed that a keratinocyte-intrinsic mechanism linking TNF, NFKB, ERK (MAPK3; 601795), and STAT3 signaling is involved in the initiation of psoriasis-like skin inflammation.
By molecular modeling, followed by experimental validation, Albogami et al. (2021) identified key residues in the PLAD of TNFR1 that were involved in PLAD-PLAD interactions to form dimer and trimer complexes. Analysis with purified recombinant proteins revealed that wildtype PLAD functioned as an antagonist of TNFR1 activity with regard to induction of cytotoxicity and cell death, as well as activation of inflammatory signaling pathways. Comparatively, PLAD with mutations at key residues showed less or even more antagonistic activity against TNFR1.
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 familial periodic fever syndrome (FPF; 142680), also known as TNF receptor-associated periodic fever syndrome (TRAPS), is characterized by episodes of fever, severe localized inflammation, and erythema. In affected individuals from 7 families with FPF, 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 one 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.
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 to be 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.
Association with Multiple Sclerosis
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.
Gregory et al. (2012) investigated a SNP in the TNFRSF1A gene that was discovered through genomewide association studies (GWASs) to be associated with MS but not with other autoimmune conditions such as rheumatoid arthritis (180300), psoriasis (see 177900), or Crohn disease (266600). By analyzing multiple sclerosis GWAS data in conjunction with the 1000 Genomes Project data, Gregory et al. (2012) provided genetic evidence that strongly implicated rs1800693 as the causal variant in the TNFRSF1A region. Gregory et al. (2012) further substantiated this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNRF1 variant mimics the effect of TNF-blocking drugs.
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.
Because their association study suggested a role for TNFR1 in aging-dependent atherosclerosis (108725), Zhang et al. (2010) grafted carotid arteries from 18- and 2-month-old wildtype and Tnfr1-/- mice into congenic apolipoprotein E (APOE; 107741)-deficient (Apoe-/-) mice and harvested grafts from 1 to 7 weeks postoperatively. Aged wildtype arteries developed accelerated atherosclerosis associated with enhanced TNFR1 expression, enhanced macrophage recruitment, reduced smooth muscle cell proliferation and collagen content, augmented apoptosis, and plaque hemorrhage. In contrast, aged Tnfr1-/- arteries developed atherosclerosis that was indistinguishable from that in young Tnfr1-/- arteries and significantly less than that observed in aged wildtype arteries. The authors concluded that TNFR1 polymorphisms were associated with aging-related CAD in humans, and that TNFR1 contributes to aging-dependent atherosclerosis in mice.
In 13 affected members of the prototype Irish/Scottish family with familial Hibernian fever (142680) reported by Williamson et al. (1982), McDermott et al. (1999) demonstrated a G-to-A transition in the TNFRSF1A gene, resulting in the substitution of tyrosine for cysteine at residue 33. In 1 branch of this family, 3 individuals reported to have periodic fevers did not possess this substitution, but they also did not share the microsatellite haplotype present in all other affected members, and the diagnosing physician had not witnessed the attacks of any of these 3 individuals.
In 8 of 8 affected members of an Irish family from the familial Hibernian fever (142680) linkage study (McDermott et al., 1998), McDermott et al. (1999) identified a mutation in the TNFRSF1A gene, leading to the substitution of methionine for threonine at residue 50. Two additional members of this family who had mild symptoms proved also to have this mutation. The 1 available member of a French-Canadian family had the same mutation.
In 2 affected members of an Irish-American family with periodic fever (142680), McDermott et al. (1999) found a mutation in the TNFRSF1A gene leading to the substitution of arginine for cysteine at residue 30 (relative to the signal peptide cleavage site).
In 3 affected members of an Irish/English/German family with periodic fever (142680), McDermott et al. (1999) identified a G-to-T transversion in the TNFRSF1A gene, leading to the substitution of phenylalanine for cysteine at residue 52.
In all 7 available members of the Australian family of Scottish ancestry with periodic fever (142680) studied by Mulley et al. (1998), McDermott et al. (1999) identified a mutation at nucleotide 349, resulting in the substitution of arginine for cysteine at residue 88.
In all 4 affected members of a Finnish family with periodic fever (142680) studied by Karenko et al. (1992), McDermott et al. (1999) demonstrated a G-to-A transition at nucleotide 350, resulting in the substitution of tyrosine for cysteine at residue 88.
In a 2-generation Dutch family with periodic fever (142680), Aganna et al. (2001) demonstrated a G-to-C transversion in exon 4 of the TNFRSF1A gene, resulting in the substitution of proline for arginine at residue 92 (R92P). The mutation was present in the affected father and in all of his 4 children (the affected proposita, a mildly affected son, and 2 unaffected children) but was not found in 120 control chromosomes from unaffected Dutch individuals. Low soluble plasma levels of TNFRSF1A segregated with the mutation in all the children, including those who were unaffected. The authors raised the possibility that low levels of soluble TNFRSF1A in combination with particular environmental insults may be necessary to produce the full-blown phenotype.
Dode et al. (2000) observed the cys30-to-ser (C30S) mutation in a French family with periodic fever (142680); Aksentijevich et al. (2001) found the same mutation in an Irish American family with 3 affected members. The cys30-to-arg mutation (191190.0003) in the same codon had been previously reported.
Aksentijevich et al. (2001) found the cys33-to-gly mutation in a father and daughter with periodic fever (142680) originally from Puerto Rico. They had histories of recurrent fever, abdominal pain, and arthralgia since birth and had been treated with corticosteroids for many years. The father had developed progressive hepatic amyloidosis, eventually necessitating liver transplantation. The cys33-to-tyr mutation (191190.0001) in the same codon had been previously reported.
In a 3-generation northern Irish family with periodic fever (142680), Aganna et al. (2003) identified a 3-bp deletion at nucleotide 211 in exon 3 of the TNFRSF1A gene. The mutation was associated with AA amyloidosis in 3 family members. The authors stated that this was the first amino acid deletion to be identified in this disorder.
In a 2-generation Japanese family with periodic fever (142680), Aganna et al. (2003) identified a 295T-A transversion in exon 3 of the TNFRSF1A gene, resulting in a cys70-to-ser (C70S) substitution. The authors stated that this was the first report of TNF receptor-associated periodic fever in a patient from the Far East.
In a patient with periodic fever syndrome (142680), Wildemann et al. (2007) identified a heterozygous cys55-to-ala (C55A) substitution in exon 2 of the TNFRSF1A gene. The patient had experienced recurrent attacks of fever, myalgias, and painful migratory rashes since childhood. At age 38, he developed brainstem and cerebellar symptoms from a T-cell predominant inflammatory infiltrate without evidence of demyelination. The findings were consistent with CNS involvement in TRAPS. Treatment with a TNF-alpha antagonist resulted in marked clinical improvement with mild residual symptoms.
Gregory et al. (2012) investigated the contribution of the single-nucleotide polymorphism (SNP) rs1800693 to susceptibility to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810). The SNP rs1800693 is proximal to the TNFRSF1A exon 6/intron 6 boundary, and the G risk allele resulted in skipping of exon 6 in minigene splicing assays. In primary human immune cells, the presence of the risk allele correlated with increased expression of transcripts lacking exon 6. TNFR1 exon 6 skipping results in a frameshift and a premature stop codon, which translates into a protein comprising only the amino-terminal 183 amino acids of TNFR1 followed by a novel 45 amino acid sequence, as confirmed by tandem mass spectrometry. This mutant protein, delta-6-TNFR1, lacks the extracellular carboxy-terminal portion of the fourth cysteine-rich domain of the select protein, the transmembrane domain, and the intracellular region that is essential for appropriate subcellular localization. The mutant protein demonstrated a more diffuse intracellular distribution than the normal localization to the Golgi apparatus. Gregory et al. (2012) found no significant spontaneous NF-kappa-B (see 164011) signaling or TNFR1-mediated apoptosis upon delta-6-TNFR1 expression. However, the mutant protein could potentially retain some intracellular activity by accumulating in the endoplasmic reticulum and evoking a stress response. Gregory et al. (2012) concluded that the combined genetic and functional analyses strongly implicated rs1800693 as the causal SNP in the MS-associated TNFRSF1A region. Because the delta-6-TNFR1 protein is soluble and capable of TNF antagonism, Gregory et al. (2012) concluded that their evidence was consistent with the reported worsening of MS upon anti-TNF therapy.
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