significantMechanismApril 1, 2011

Misfolded TNFRSF1A protein shown to activate unfolded protein response and ROS

TNF Receptor-Associated Periodic Syndrome →

Summary

Bulua et al. (2011) and Simon et al. (2010) demonstrated that structural TNFRSF1A mutations cause receptor misfolding and retention in the endoplasmic reticulum, triggering the unfolded protein response and mitochondrial ROS production. This ER stress pathway activates MAPK signaling and NF-kB independent of TNF ligand, explaining why anti-TNF therapy is less effective than IL-1 blockade in TRAPS.

High-penetrance pathogenic variants. Disrupt disulfide bonds in CRD1/CRD2 of the TNFR1 extracellular domain. Associated with severe phenotype and high amyloidosis risk (24% vs 2% for non-cysteine).

TNFRSF1AT50M (p.Thr79Met)

Most common high-penetrance pathogenic variant. Affects a conserved hydrogen bond critical for protein folding in CRD1. Despite not disrupting a cysteine, carries high disease penetrance and amyloidosis risk similar to cysteine mutations.

TNFRSF1AR92Q (p.Arg121Gln)

Low-penetrance variant of uncertain pathogenic significance. Present in 1.2–4% of healthy Caucasians. Associated with milder disease, shorter episodes, less familial aggregation (19% vs 64%), and higher spontaneous resolution rates. Classified as INSAID Group B (uncertain significance).

TNFRSF1AP46L (p.Pro75Leu)

Another low-penetrance variant. Found at high frequency in sub-Saharan West African populations. Clinical significance debated — may be a benign polymorphism in some ethnic backgrounds.