title: Candidate genes in patients with autoinflammatory syndrome resembling tumor necrosis factor receptor-associated periodic syndrome without mutations in the TNFRSF1A gene.
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.
  
  
  CONCLUSIONS
  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.
authors: Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy.
authors: Silvia
authors: S
authors: Borghini
authors: Michele
authors: M
authors: Fiore
authors: Marco
authors: M
authors: Di Duca
authors: Francesco
authors: F
authors: Caroli
authors: Martina
authors: M
authors: Finetti
authors: Giuseppe
authors: G
authors: Santamaria
authors: Francesca
authors: F
authors: Ferlito
authors: Federico
authors: F
authors: Bua
authors: Paolo
authors: P
authors: Picco
authors: Laura
authors: L
authors: Obici
authors: Alberto
authors: A
authors: Martini
authors: Marco
authors: M
authors: Gattorno
authors: Isabella
authors: I
authors: Ceccherini
mesh_terms: D000328:Adult; D000626:Aminopeptidases / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D000080866:Nucleobindins; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C512817:CA11 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000630650:NUCB2 protein, human; D009419:Nerve Tissue Proteins; D000080866:Nucleobindins; C510272:RBMX protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; C117046:TNIP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D000626:Aminopeptidases; C464841:ERAP1 protein, human