Tumor Necrosis Factor Receptor Superfamily Member 1A Research Articles

TNF receptor-associated periodic fever syndrome caused by sequence alterations in exonic splicing enhancers: comment on the article by Trübenbach et al.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), an autosomal disease belonging to human autoinflammatory syndromes, is caused by mutations in Tumor Necrosis Factor Receptor Superfamily Member 1A (TNFRSF1A) gene. Trübenbach and colleagues described a patient with two heterozygotic nucleotide transversions in exon 4 of TNFRSF1A gene: the first is a substitution from guanine to cytosine at position 263 of the nucleotide sequence (c.263 G>C); the second is a substitution from cytosine to adenine at position 264 (c.264 C>A); the two mutations affect the amino acid number 88 of the protein. To date, this was the first report of a double monoallelic mutation in a gene related to autoinflammatory syndromes. Using two web interfaces (ESEfinder and RESCUE-ESE), we provide evidence that the double nucleotide change may affect an exonic splicing enhancer (ESE), a sequence element distinct from the canonical splice sites that are needed for normal splicing. ESEs are short and degenerate sequences found within coding exons and required for efficient splicing and splice site recognition. In order to verify if these changes really affect an ESE, it would be useful to analyze the described index case TNFRSF1A cDNA, because if this analysis will evidence an exon skipping in the TNFRSF1A coding sequence, it would then represent the first mutation in autoinflammatory syndromes demonstrated to be caused by ESE elements alteration.

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A); interferon regulatory factor 8 (IRF8); CD6

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A); interferon regulatory factor 8 (IRF8); CD6

59: TNF-α and TNF Receptor Superfamily Member 1B Polymorphisms Predict Risk of Acute GVHD Following Matched Unrelated Donor BMT in Children

Tumor necrosis factor-alpha (TNF-α) plays a significant role in the conditioning related toxicities and development of acute GvHD (aGvHD). In this study, we sought to examine if specific polymorphisms in TNF pathway genes were associated with risk of aGvHD. Single nucleotide polymorphisms (SNPs) in TNF-α; and TNF receptor superfamily member 1A (TNFRSF1A) and 1B (TNFRSF1B) were investigated; we selected SNPs with minor allele frequency of ≥10% (13 in all) and TNF-α d microsatellite. In a multi-institutional trial, 180 eligible patients (mean age 10 y, median 11, range 6 m-20 y) were prospectively evaluated for clinical outcomes after 6/6 matched unrelated donor marrow transplants.

Mutant tumor necrosis factor receptor associated with tumor necrosis factor receptor–associated periodic syndrome is altered antigenically and is retained within patients' leukocytes

To investigate the effect of mutations in tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in TNFR-associated periodic syndrome (TRAPS) on the binding of anti-TNFRSF1A monoclonal antibodies (mAb), and to investigate the subcellular distribution of mutant versus wild-type (WT) TNFRSF1A in patients with TRAPS. HEK 293 cells transfected with WT and/or mutant TNFRSF1A were used to investigate the interaction of anti-TNFRSF1A mAb with the WT and mutant proteins. Monoclonal antibodies that differentially bound to C33Y TNFRSF1A were used to investigate the distribution of WT and mutant TNFRSF1A in TRAPS patients with the C33Y mutation. We identified a mAb whose binding to TNFRSF1A was completely abolished by the C33Y or C52F TRAPS-associated mutations, whereas other mutations (T50M, C88Y, R92Q) had lesser effects on the binding of this mAb. A different mAb was found to bind efficiently to all of the mutant forms of TNFRSF1A examined as well as to the WT receptor. Exploitation of the differential binding properties of these mAb indicated that mutant (as distinct from WT) TNFRSF1A showed abnormal intracellular retention in the neutrophils of TRAPS patients with the C33Y mutation, with little if any expression of mutant TNFRSF1A on the cell surface or as soluble receptor in plasma. TRAPS-associated mutant TNFRSF1A has an antigenically altered structure and shows abnormal retention in the leukocytes of patients with TRAPS, which is consistent with previous findings from in vitro and transgenic model systems. This is consistent with a misfolded protein response contributing to the pathophysiology of TRAPS.

TNF receptor I polymorphism is associated with persistent palindromic rheumatism

Objectives: To investigate the association between tumour necrosis factor‐α (TNFα), TNF receptor superfamily member 1A (TNFRSF1A, also known as TNFRI), TNFRSF1B (TNFRII), and interleukin‐1β (IL‐1β) single nucleotide polymorphisms (SNPs) and the susceptibility to persistent palindromic rheumatism (PR).Methods: Fifty‐six unrelated patients with persistent PR and 100 unrelated healthy controls were genotyped for TNFα −308G/A, −238G/A, and +488G/A, TNFRSF1A −609G/T and +36A/G, TNFRSF1B +676T/G and +1663G/A, and IL‐1β −511C/T, −31T/C, and +3954C/T using real‐time polymerase chain reaction (RT‐PCR).Results: The TNFRSF1A +36G allele [odds ratio (OR) = 3.94, p = 0.003, corrected p (pc) = 0.03] and the TNFRSF1A +36AG genotype (OR = 4.81, p = 0.002, pc = 0.04) were significantly associated with persistent PR. The frequency of TNFRSF1B +676T/+1663A was increased in PR patients (OR = 2.12, p = 0.01), but failed to reach statistical significance after Bonferroni correction. No correlation was observed between persistent PR and TNFα, TNFRSF1A −609G/T, or IL‐1β SNPs.Conclusions: The results of this study provide evidence of an association between persistent PR and SNPs within the TNFRSF1A gene, and suggest that TNFRI is involved in the aetiopathogenesis of PR.

Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively

The importance of tumor necrosis factor (TNF)-alpha and the TNF receptor gene polymorphisms in the etipathogenesis of inflammatory bowel disease (IBD) has not been elucidated. DNA from peripheral blood samples was obtained from 124 patients with Crohn's disease (CD), 106 patients with ulcerative colitis (UC), and 111 unrelated healthy controls. We examined two single nucleotide polymorphisms (SNPs) of the TNF-alpha gene, TNF (-308 G/A and -238 G/A), an SNP of the TNF receptor superfamily member 1A gene, TNFRSF1A(also known as TNFR1), at codon 12 in exon 1 (CCA/CCG), and two SNPs of the 1B gene, TNFRSF1B (also known as TNFR2), (1466 A/G and 1493 C/T). There was a difference in the carrier frequency for haplotype AG (-308 A, -238 G) between UC patients and the controls (OR=4.76, 95% CI=1.53-14.74, P<0.01). We found a significant difference in carrier frequency for haplotype AT (1466 A, 1493 T) of the TNFRSF1B gene between CD patients and the controls (OR=2.13, 95% CI=1.08-4.21, P<0.05). The significance proved to be greater in CD patients with both internal and external fistula (OR=4.8, 95% CI=1.73-13.33, P<0.01), and in those who were poor responders ( n=22) to our treatments, which consisted of nutritional therapy, medical therapy and surgical therapy (OR=9.24, 95% CI=3.37-25.36, P<0.001). This study suggests that one of the genes responsible for UC may be the TNF gene, or an adjacent gene, and that TNFRSF1B gene polymorphisms contribute greatly to the increased onset risk of CD and to the disease behavior.