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.
OBJECTIVE
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 TNFalpha 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. TNFalpha-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.
Stojanov
S
S
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. stojanos@mail.nih.gov
Dejaco
C
C
Lohse
P
P
Huss
K
K
Duftner
C
C
Belohradsky
B H
BH
Herold
M
M
Schirmer
M
M
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000276:immunology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology; D004252:DNA Mutational Analysis / Q000379:methods; D000068800:Etanercept; D010505:Familial Mediterranean Fever / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology; D009154:Mutation; D010375:Pedigree; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept