Alt. symbols: TNFR1 | TNF-R | TNFAR | TNFR60 | TNF-R-I | CD120a | TNF-R55

Approved name: TNF receptor superfamily member 1A
Alt. names: tumor necrosis factor receptor superfamily, member 1A

Location: 12p13.31: 6328757 - 6342114 (-)
Gene type: protein_coding, 18 transcripts.

Scores: LoFtool: 0.032700 | pLI: 0.98547605 | LOEUF: 0.236

HGNC: 11916

NCBI: 7132, RefSeq: NG_007506.1

Ensembl: ENSG00000067182.9

LRG_193 | Status: public

OMIM: 191190

Expression | ProteinAtlas

TNFRSF1A encodes the tumor necrosis factor receptor 1 (TNFR1) protein. TNFR1 is a transmembrane protein that binds to the tumor necrosis factor (TNF) in the extracellular space. The interaction of TNF with TNFR1 causes TNFR1 to bind to two other TNFR1 proteins, forming a trimeric complex, which is necessary for the TNFR1 receptor to be functional. TNF binding also triggers an intracellular signalling cascade from the TNFR1 that leads either to inflammation or apoptosis. This signalling cascade initiates the NFkB pathway, which triggers inflammation and leads to cytokine production. Apoptosis is initiated when the TNFR1, bound to TNF, is internalized and starts a process known as the caspase cascade.

Monoallelic TNFRSF1A mutations are associated with AD TRAPS (TNF-receptor-associated periodic syndrome) [OMIM: 142680], as well as with increased susceptibility to multiple sclerosis [OMIM: 614810]. TRAPS attacks last longer than those of FMF, generally more than 5 days and up to 3 weeks, although attacks shorter than 5 days have been reported (PMID: 23965844). Abdominal pain, often resembling a surgical acute abdomen, is reported by almost all patients, often in association with fever, migrator y myalgias and overlying tender erythematous macular, edematous or urticarial skin rash. Nearly 3/4 of cases develop skin manifestations, including urticaria-like lesions, plaques, and patches. Around 30-50% of patients may have ocular manifestations (periorbital edema, recurrent conjunctivitis or anterior uveitis), serositis, and/or arthritis. Neurological manifestations are rare but secondary renal amyloidosis can affect up to 64% of patients (PMID: 10199409, 23280696), and those with mutations in cysteine residues are particularly at risk (PMID: 12352631). Increased inflammatory marker levels during symptom-free intervals may help identify patients at greatest risk of developing this complication. A perivascular and interstitial lymphocyte and monocyte/macrophage infiltrate may be seen on histopathology from skin lesions. More than 60 mutations in TNFRSF1A have been reported to cause TRAPS, most of which are missense mutations involving cysteine residues that participate in disulfide bonding. The disease-causing substitutions result in misfolded TNF receptor, which accumulate and aggregate within the endoplasmic reticulum (ER) rather than being transported towards the plasma membrane. These aggregates of misfolded protein result in constitutive, inappropriate activation of the unfolded protein response independently of extracellular ligand binding, resulting in hypersecretion of pro-inflammatory cytokines such as IL-1beta and chronic inflammation. It remains unclear how disruption of the apoptosis pathway contributes to the pathogenesis of TRAPS. Penetrance is also thought to be incomplete, as some TNFRSF1A mutation carriers only develop mild disease or remain asymptomatic. Therefore, additional genetic changes or environmental factors likely contribute to the development of TRAPS. Colchicine, the treatment of choice for FMF, is ineffective in TRAPS. TRAPS patients also respond poorly to TNF inhibition (PMID: 16935919) but do improve with IL-1 blockade (PMID: 28536823, 27474763, 34527082, 28454496), confirming an important role for IL-1 in the pathogenesis of this condition. [Load More]