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

J Rheumatol. 2011 Jul;38(7):1378-84. doi: 10.3899/jrheum.101260. Epub 2011 Apr 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aminopeptidases / genetics
  • Apoptosis / physiology
  • Calcium-Binding Proteins / genetics
  • Case-Control Studies
  • DNA-Binding Proteins / genetics
  • Familial Mediterranean Fever / genetics*
  • Familial Mediterranean Fever / physiopathology*
  • Female
  • Hereditary Autoinflammatory Diseases / genetics*
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Humans
  • Male
  • Minor Histocompatibility Antigens
  • Mutation / genetics*
  • NF-kappa B / physiology
  • Nerve Tissue Proteins / genetics
  • Nucleobindins
  • Phenotype
  • Receptors, Tumor Necrosis Factor, Type I / genetics*
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • CA11 protein, human
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • NUCB2 protein, human
  • Nerve Tissue Proteins
  • Nucleobindins
  • RBMX protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • TNIP1 protein, human
  • Tumor Necrosis Factor-alpha
  • Aminopeptidases
  • ERAP1 protein, human