Candidate genes in patients with autoinflammatory syndrome resembling tumor necrosis factor receptor-associated periodic syndrome without mutations in the TNFRSF1A gene.

Objective: Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant multisystemic autoinflammatory condition. Patients display different mutations of the TNF receptor superfamily 1A gene (TNFRSF1A), coding for a nearly ubiquitous TNF receptor (TNFR1). No TNFRSF1A mutation has been identified in a proportion of patients with TRAPS-like phenotype.

Methods: We investigated mechanisms downregulating the TNF-induced inflammatory response such as (1) receptor shedding, producing a secreted form acting as a TNF inhibitor; (2) receptor internalization with subsequent induction of apoptosis; and (3) negative regulation of nuclear factor-κB (NF-κB) transcription. We analyzed the sequence of genes known to play a pivotal role in these pathways, in 5 patients with TRAPS symptoms and showing shedding and/or apoptosis defects, but without mutations of the TNFRSF1A gene.

Results: Sequence analysis of 3 genes involved in TNFR1 shedding (ERAP1, NUCB2, RBMX) and 3 genes involved in negative regulation of NF-κB signaling (TNFAIP3, CARP-2) or NF-κB transcription (ZFP36) revealed only a few unreported variants, apparently neutral.

Conclusion: Our study rules out any involvement in the pathogenesis of TRAPS of some of the genes known to regulate TNFR1 shedding and TNF-induced NF-κB signaling and transcription. Gene(s) responsible for TRAPS-like syndrome remain to be investigated among currently unidentified genes likely involved in these pathways, or by applying the genome-wide function-free sequencing approach.