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Clinical and functional characterization of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with TNF receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment
  1. Silvia Stojanov (stojanos{at}mail.nih.gov)
  1. National Institutes of Health, United States
    1. Christian Dejaco (christian.dejaco{at}ekh.at)
    1. Innsbruck Medical University, Austria
      1. Peter Lohse (peter.lohse{at}med.uni-muenchen.de)
      1. University of Munich, Germany
        1. Kristina Huss (kristina.huss{at}med.uni-muenchen.de)
        1. Children's Hospital, University of Munich, Germany
          1. Christina Duftner (christina.duftner{at}ekh.at)
          1. Innsbruck Medical University, Austria
            1. Bernd H. Belohradsky (bernd.belohradsky{at}med.uni-muenchen.de)
            1. Children's Hospital, University of Munich, Germany
              1. Manfred Herold (manfred.herold{at}i-med.ac.at)
              1. Innsbruck Medical University, Austria
                1. Michael Schirmer (michael.schirmer{at}ekh.at)
                1. Innsbruck Medical University, Austria

                  Abstract

                  Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumor necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site.

                  Methods: Patients with symptoms suggestive of TRAPS and twenty-two healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by enzyme-linked immunosorbent assays. 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 TNF-α in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS.

                  Results: TNFRSF1A sequencing revealed 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 a 18 months 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. TNF-α-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 play a pathogenetic role in affected patients.

                  • <it>TNFRSF1A</it> cleavage site mutation
                  • TNF receptor-associated periodic fever syndrome
                  • TRAPS
                  • cardiovascular complications
                  • etanercept

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