TNFRSF1A Gene: Function, Mutations, and Associated Diseases | NCBI, UniProt, OMIM

TNFRSF1A (TNF Receptor Superfamily Member 1A) encodes tumor necrosis factor receptor 1 (TNFR1), a transmembrane receptor that mediates the majority of cellular responses to TNF-alpha. Binding of TNF-alpha to TNFR1 triggers multiple signaling pathways, including NF-kB activation, MAPK cascades, and apoptosis. The receptor contains a death domain in its cytoplasmic region, essential for recruiting adaptor proteins such as TRADD. Mutations in TNFRSF1A are associated with TNF receptor-associated periodic syndrome (TRAPS), an autosomal dominant autoinflammatory disorder characterized by recurrent fevers and systemic inflammation.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• TNF signaling pathway (KEGG hsa04668)

• NF-kB signaling pathway (Reactome R-HSA-73887)

• Apoptosis (Reactome R-HSA-109581)

• TNFR1-mediated signaling (Reactome R-HSA-3371378)

TNFRSF1A encodes TNFR1 (UniProt P19438), a 455-amino-acid type I transmembrane glycoprotein. The extracellular domain contains four cysteine-rich repeats responsible for TNF-alpha binding. The intracellular region includes a death domain (residues 326–414) that recruits TRADD upon ligand binding. TNFR1 is expressed on most cell types and is the primary mediator of TNF-induced inflammation, cell survival, and cell death. Soluble TNFR1 (sTNFR1) is generated by proteolytic shedding and acts as a natural TNF inhibitor. Mutations in TNFRSF1A cause TRAPS, and the gene is also implicated in autoimmune and infectious diseases.