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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.

Abstract

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 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.

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  • Authors+Show Affiliations

    ,

    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

    , , , , , ,

    Source

    Annals of the rheumatic diseases 67:9 2008 Sep pg 1292-8

    MeSH

    Adolescent
    Adult
    Amino Acid Sequence
    Anti-Inflammatory Agents, Non-Steroidal
    Apoptosis
    Base Sequence
    CD4-Positive T-Lymphocytes
    CD8-Positive T-Lymphocytes
    Cardiovascular Diseases
    Cells, Cultured
    Cellular Senescence
    DNA Mutational Analysis
    Etanercept
    Familial Mediterranean Fever
    Female
    Humans
    Immunoglobulin G
    Male
    Middle Aged
    Molecular Sequence Data
    Monocytes
    Mutation
    Pedigree
    Receptors, Tumor Necrosis Factor
    Receptors, Tumor Necrosis Factor, Type I
    Receptors, Tumor Necrosis Factor, Type II
    T-Lymphocyte Subsets
    Treatment Outcome
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    18180277

    Citation

    Stojanov, S, et al. "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." Annals of the Rheumatic Diseases, vol. 67, no. 9, 2008, pp. 1292-8.
    Stojanov S, Dejaco C, Lohse P, et al. 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. Ann Rheum Dis. 2008;67(9):1292-8.
    Stojanov, S., Dejaco, C., Lohse, P., Huss, K., Duftner, C., Belohradsky, B. H., ... Schirmer, M. (2008). 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. Annals of the Rheumatic Diseases, 67(9), pp. 1292-8. doi:10.1136/ard.2007.079376.
    Stojanov S, et al. 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. Ann Rheum Dis. 2008;67(9):1292-8. PubMed PMID: 18180277.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Stojanov,S, AU - Dejaco,C, AU - Lohse,P, AU - Huss,K, AU - Duftner,C, AU - Belohradsky,B H, AU - Herold,M, AU - Schirmer,M, Y1 - 2008/01/07/ PY - 2008/1/9/pubmed PY - 2008/10/29/medline PY - 2008/1/9/entrez SP - 1292 EP - 8 JF - Annals of the rheumatic diseases JO - Ann. Rheum. Dis. VL - 67 IS - 9 N2 - 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 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. SN - 1468-2060 UR - https://www.unboundmedicine.com/medline/citation/18180277/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_ L2 - http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=18180277 DB - PRIME DP - Unbound Medicine ER -