Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)

Abstract

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary disease, caused by heterozygous mutations in TNFRSF1A, which encodes for TNF-receptor 1 (TNFR1). Most of the pathogenic mutations are single-nucleotide missense variants localized in extracellular, cysteine rich domains of the receptor. The pathogenesis of TRAPS is complex and likely involves several mutually non-exclusive molecular mechanisms, however, co-expression of the mutated and wild type of the receptor is required in all cases. The proposed mechanisms include abnormal TNFR1 cleavage; increased activation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase; ligand-independent activation of mutant TNFR1; generation of mitochondrial reactive oxygen species (ROS) leading to enhanced activation of the NLRP3 inflammasome; TNFR1 misfolding and retention within the endoplasmic reticulum (ER) leading to activation of ER-associated endonuclease, inositol-requiring enzyme 1 (IRE-1) and resulting in hyper-responsiveness to lipopolysaccharide via selective degradation of microRNAs (miRs).