Stojanov, S.; Dejaco, C.; Lohse, Peter; Huss, Kristina; Duftner, C.; Belohradsky, B.H.
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.
In: Annals of the Rheumatic Diseases, Vol. 67: S. 1292-1298
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
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 TNFa in the presence of cycloheximide
and annexin V staining. T cell phenotypes were monitored
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. TNFa-induced apoptosis of PBMCs and T-cell
senescence were comparable between V173D patients
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.