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.

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.

• Authors: 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
• Journal: The Journal of rheumatology (J Rheumatol) Vol. 38 Issue 7 Pg. 1378-84 (Jul 2011) ISSN: 0315-162X [Print] Canada
• PMID: 21459945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adult
• Aminopeptidases (genetics)
• Apoptosis (physiology)
• Calcium-Binding Proteins (genetics)
• Case-Control Studies
• DNA-Binding Proteins (genetics)
• Familial Mediterranean Fever (genetics, 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)