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

Silvia Borghini, Michele Fiore, Marco Di Duca, Francesco Caroli, Martina Finetti, Giuseppe Santamaria, Francesca Ferlito, Federico Bua, Paolo Picco, Laura Obici, Alberto Martini, Marco Gattorno, Isabella Ceccherini

Research output: Contribution to journalArticle


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. The Journal of Rheumatology

Original languageEnglish
Pages (from-to)1378-1384
Number of pages7
JournalJournal of Rheumatology
Issue number7
Publication statusPublished - Jul 2011



  • Candidate gene screening
  • CARP-2
  • TNFR1 shedding
  • Tumor necrosis factor receptor-associated periodic syndrome
  • ZFP36

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy

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