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The gene coding for the type I (p55) tumor necrosis factor receptor (TNF-R1) has been localized on human chromosome 12, band 12p13.2, by in situ hybridisation using a biotinylated genomic probe.
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... Apoptosis is increased in chronic inflammatory diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and pSS (Bayley et al., 2003;Szodoray et al., 2004;Valle et al., 2010;Corona-Sanchez et al., 2012). TNFR1 receptor is a type I transmembrane glycoprotein (Derré et al., 1991;Storey et al., 2002). Various studies have reported high sTNFR1 (soluble TNFR1) levels in the serum of AS, SLE, and AR patients. ...
... TNFR1 is encoded by the TNFR1 gene with its locus located at 12p13.2 (Derréet al., 1991;Xanthoulea et al., 2004). The TNFR1 gene contains 10 exons and 9 introns (Derré et al., 1991). Various polymorphisms have been described in the promoter region that could modify the transcription rate. ...
... Table 3. Genotypic and allelic frequency of TNFR1-383 A˃C in patients with pSS and HS. RF and CRP levels were high in pSS patients; these results are similar with other previous reports in pSS patients (Derré et al., 1991;Szodoray et al., 2004;Ramos-Casals and Font, 2005;Valle et al., 2010;Corona-Sanchez et al., 2012). Anti-Ro and anti-La antibodies levels were similar to those reported by Hammi, et al. and Szododay, et al. and are related to the autoimmune process (Szodoray et al., 2004;Hammi et al., 2005). ...
Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the-383 in promoter region position. The TNFR1-383 A˃C polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 A˃C polymorphism and TNFR1 soluble (sTNFR1) levels and 2 A.L. Fletes-Rayas et al. ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 15 (2): gmr.15024177 laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the A˃C genotype were observed. In these patients, the SSDAI score was higher than in A˃A genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 A˃C polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in A˃C genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 A˃C polymorphism.
... Apoptosis is increased in chronic inflammatory diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and pSS (Bayley et al., 2003;Szodoray et al., 2004;Valle et al., 2010;Corona-Sanchez et al., 2012). TNFR1 receptor is a type I transmembrane glycoprotein (Derré et al., 1991;Storey et al., 2002). Various studies have reported high sTNFR1 (soluble TNFR1) levels in the serum of AS, SLE, and AR patients. ...
... TNFR1 is encoded by the TNFR1 gene with its locus located at 12p13.2 (Derréet al., 1991;Xanthoulea et al., 2004). The TNFR1 gene contains 10 exons and 9 introns (Derré et al., 1991). Various polymorphisms have been described in the promoter region that could modify the transcription rate. ...
... Table 3. Genotypic and allelic frequency of TNFR1-383 A˃C in patients with pSS and HS. RF and CRP levels were high in pSS patients; these results are similar with other previous reports in pSS patients (Derré et al., 1991;Szodoray et al., 2004;Ramos-Casals and Font, 2005;Valle et al., 2010;Corona-Sanchez et al., 2012). Anti-Ro and anti-La antibodies levels were similar to those reported by Hammi, et al. and Szododay, et al. and are related to the autoimmune process (Szodoray et al., 2004;Hammi et al., 2005). ...
Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the -383 in promoter region position. The TNFR1-383 A˃C polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 A˃C polymorphism and TNFR1 soluble (sTNFR1) levels and laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the A˃C genotype were observed. In these patients, the SSDAI score was higher than in A˃A genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 A˃C polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in A˃C genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 A˃C polymorphism.
... The mutations in exon 2-3 and 4-5 of the TNFRSF1A gene which is located on chromosome 12p13.2 [16] are the cause of this rare syndrome. TNFRSF1A gene encodes the 55 kDa receptor for tumor necrosis factor [17]. ...
Adult onset Still's disease (ASD) is a systemic inflammatory disorder of unknown etiology. ASD is characterized by fever with unknown etiology, rash, arthritis, and involvement of several organ systems. FMF and TRAPS are two important autoinflammatory diseases which characterized with recurrent inflammatory attacks. We aimed in this study to investigate the MEFV gene and TNFRSF1A gene variations in ASD. Twenty consecutive Turkish ASD patients (14 female and 6 male; mean age 38.45 ± 14; mean disease duration 3.3 ± 2.3; mean age of the disease onset 35.1 ± 14.4) and 103 healthy controls of Turkish origin were analyzed. All ASD patients were genotyped for the 4 MEFV mutations (M694V, E148Q, V726A, M680I) and TNFRSF1A gene exon 2-3 and exon 4-5 by using sequence analysis. The healthy controls are genotyped using PCR-RFLP method for intron 4 variation. The results of MEFV gene mutations screening show an increase in the MEFV mutation rate in ASD group, but it was not significantly different (p = 0.442, OR 1.64, 95 % CI 0.409-6.589). T-C polymorphism (rs1800692) was the only variation in the intron 4 of TNFRSF1A gene that we observed at the ASD patients. The frequency of TT genotype was 15 %, TC: 45 %, and CC: 40 % in ASD patients and the frequencies were 22, 41, and 37 % in healthy controls, respectively. When we analyzed the allele difference between both groups, there was no difference (p = 0.54, OR 1.24, 0.619-2.496-2.654). The variations in MEFV may have role in ASD pathogenesis. Our findings suggest that there is no significant association between ASD and TNFRSF1A variations.
... It is caused by mutations in exons 2-3 and 4-5 of the TNFRSF1A gene on chromosome 12p13.2 [3]. TNFRSF1A gene encodes the 55-kDa receptor for tumor necrosis factor [4]. ...
Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominantly inherited rare autoinflammatory disease. It is caused by mutations in exons 2-3 and 4-5 of the tumor necrosing factor receptor superfamily 1A (TNFRSF1A) gene on chromosome 12p13.2. TNFRSF1A gene encodes the 55-kDa receptor for tumor necrosis factor. Attacks are associated with abdominal pain, myalgia, erythematous skin rash, conjunctivitis, and periorbital edema. Until now, more than 80 mutations have been identified. We herein report three patients with TRAPS of Turkish origin. The patients were followed up in our outpatient clinic in Kocaeli University Division of Rheumatology. Because of their TRAPS associated clinical features, we isolated genomic DNA from whole blood and sequenced the exon 2-3 and 4-5 third exon of TNFRSF1A gene after amplification with appropriate primers. One of the patients with TRAPS was 47-year-old female, who described recurrent attacks of fever, urticarial rash, conjunctivitis, arthralgia, myalgia, abdominal pain, thoracic pain, headache, fatigue, and elevated acute phase response since her childhood. With the sequencing of the TNFRSF1A gene, we identified heterozygous C29R mutation, which has not been reported before in any TRAPS patient. The other patients are her sons with similar findings and age 29 and 26. They were heterozygous for C29R mutation in TNFRSF1A gene too. We report novel C29R mutation in three TRAPS patients of Turkish origin, in which the main clinical features are recurrent fever attacks, erythematous skin rash, conjunctivitis, myalgia, and arthralgia. Treatment with steroids resolved the symptoms and lesions.
... as a benign course, but later secondary amyloidosis has been reported [99]. In patients who have FHF, McDermott and colleagues [100] identified germline mutations in the TNFRSF1A gene, which had been identified as a candidate gene by linkage studies [100]. The type 1 receptor (the p55 TNF receptor) is encoded by a gene located on chromosome 12p13.2 [101]. More than 82 mutations in TNFRSF1A have been associated with TRAPS so far [1], directly affecting the extracellular domains of the resultant protein. All the mutations reside in exons 2 to 4 of the 10 exons gene, and the vast majority are substitutions. TNFRSF1A is expressed in various cells [102,103] and has been shown to induce cytok ...
Human autoinflammatory diseases (except for PFAPA) are a heterogeneous group of genetically determined diseases characterized by seemingly unprovoked inflammation in the absence of autoimmune or infective causes (Table 2). The last decade has witnessed tremendous advances in the understanding of these disorders. These advances have allowed therapeutic interventions resulting in improvement in the short-term and long-term morbidity of all of these diseases. Future research into the molecular mechanisms underlying these inflammatory diseases should lead to a better understanding of inflammatory diseases in general and, it is hoped, to better and more targeted therapies.
... In patients with FHF, McDermott et al [78] identified germline mutations in the TNFRSF1A gene, which had been identified as a candidate gene by linkage studies [78]. The type 1 receptor (the p55 TNF receptor) is encoded by a gene located on chromosome 12p13.2. [79] Twenty mutations have been identified since the initial discovery of the mutations in TNF receptor superfamily 1A (TNFRSF1A). Although originally found in patients of Irish or Scottish ancestry, mutations have been reported from diverse ethnicities, suggesting that the diagnosis of TRAPS should not be excluded based on a patient's ancestry [80]. ...
Human autoinflammatory diseases are a heterogeneous group of genetically determined diseases characterized by seemingly unprovoked inflammation, in the absence of autoimmune or infective causes. These diseases are caused by proteins that involve in the innate immunity and interact with other proteins to form an inflammasome (1), which acts as an early sensor to detect danger signals and initiates the host defense reactions (2). Members of the “NALP” family of proteins (which includes cryopyrin) are components of the inflammasome. Two types of inflammasomes have now been described: the NALP1 inflammasome and the NALP3, or cryopyrin, inflammasome. The stimulation of cryopyrin triggers a series of reactions, which ultimately result in the activation of the proinflammatory cytokine interleukin-13.
The past decade has witnessed tremendous advances in the understanding of these disorders. These advances have allowed for therapeutic interventions, resulting in improvement in the short-term and long-term morbidity of all of these diseases. As these syndromes often have overlapping symptoms, diagnostic criteria are essential.
Distinctions between tumor necrosis factor, TNF-α, and lymphotoxin, TNF-β, have previously been based on the differences between their protein sequences, biological activity, and molecular regulation. In the past year, elucidation of the molecular nature of the two molecules and the interactions with common receptors has emphasized their similarities, although profound differences continue to emerge with regard to their mode of production, transcription rates, mRNA half-lives, and the importance of various DNA regulatory sequences. A role for both TNF-α and TNF-β has recently been suggested with regard to disease, particularly multiple sclerosis. The past year has also seen the description of an extensive microsatellite polymorphic system which should provide a more definitive understanding of the association of the TNF locus with disease.
The gene encoding the type II (p75) tumor necrosis factor receptor (TNF-RII) has been localized on human chromosome 1, band 1p36.2 by nonradioactive in situ hybridization. The gene encoding the type I (p55) TNF-R, which is structurally homologous to the type II (p75) TNF-R, has been previously localized on chromosome 12 band 12p13. Thus, despite their probable common ancestry, the genes for the two TNF-Rs are localized on different chromosomes.
The tumor necrosis factor (TNF)-related cytokines have emerged over the past 2 years as a large family of pleiotropic mediators of host defense and immune regulation. Members of this family exist in membrane-anchored forms acting locally through cell-to-cell contact, or as secreted proteins capable diffusion to more distant targets. A parallel family of receptors signals the presence of these molecules leading to the initiation of cell death or cellular proliferation and differentiation in the target tissue (see Smith et al. 1994; Banchereau et al. 1994 for reviews). The focus of this review is on two members of this family produced by activated T cells, the original lymphotoxin-α (LT-α, previously referred to as TNF-β), and a new member, lymphotoxin-β (LT-β), and their specific receptors. Initially discovered by cytotoxic activity in vitro, lymphotoxn, as a secreted molecule, was one of the earliest postulated mechanisms used by cytotoxic T lymphocytes (Ruddle and Waksman 1968; Granger and Williams 1868). The molecular cloning of LT and TNF dramatically revised the view of these cytokines as limited nonspecific cytotoxins and revealed their more intricate role in immunoregulation and host defense. Although once thought to be merely a redundant form of TNF, new findings have indicated that lymphotoxin has a role in immune physiology distinct from TNF and forms a system of secreted and membrane-anchored immunoregulatory molecules.
An 809-bp region at the 5' flank of the human p55 tumor necrosis factor receptor (TNF-R)-encoding gene was found to be active in driving expression of the cat reporter gene, indicating that it contains a functional promoter. Deletion analysis showed that the promoter activity is present in the region between nucleotides (nt) -385 and -207; the sequence upstream from this region (nt -809 to -385) has an inhibitory effect. The promoter for the p55 TNF-R resembles housekeeping-type promoters in that it drives transcription from multiple start points (tsp) and lacks canonical TATA and CAAT box motifs. The cluster of tsp lies in a region which is particularly C+T rich. In this region, upstream from and near to the furthest upstream tsp, two closely located TCC repeat motifs were identified. These motifs also appear twice in the promoter for the epidermal growth factor receptor, where they were shown to be essential for promoter activity. The human p55 TNF-R promoter shows an overall resemblance, yet also some marked dissimilarities, to the recently described promoter for the mouse p55 TNF-R.
