Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment
- S Stojanov1,
- C Dejaco2,3,
- P Lohse4,
- K Huss1,
- C Duftner2,3,
- B H Belohradsky1,
- M Herold2,
- M Schirmer2,3
- 1Department of Infectious Diseases and Immunology, Children’s Hospital, University of Munich, Munich, Germany
- 2Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria
- 3General Hospital of the Elisabethinen, Klagenfurt, Austria
- 4Department of Clinical Chemistry - Grosshadern, University of Munich, Munich, Germany
- Dr S Stojanov, Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 9N210, 10 Center Drive, Bethesda, MD 20892, USA;
- Accepted 20 December 2007
- Published Online First 7 January 2008
Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site.
Methods: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFα in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS.
Results: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194–14G>A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFα-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC.
Conclusions: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients.
Funding: This work was supported by the Verein zur Förderung der Hämatologie, Onkologie und Immunologie and the Verein zur Förderung der wissenschaftlichen Ausbildung und Tätigkeit an der Universität Innsbruck, Innsbruck, Austria.
Competing interests: None.
Ethics approval: The study was approved by the ethics committee of the Innsbruck Medical University, Austria.