Tumor necrosis factor receptor–associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor: Implications for pathogenesis

Kriegel, Martin; Hüffmeier, Ulrike; Scherb, Elisabeth; Scheidig, Christina; Geiler, Thomas; Kalden, Joachim R.; Reis, André; Lorenz, Hanns‐Martin

doi:10.1002/art.11169

Cited by 42 publications

(19 citation statements)

References 7 publications

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“…The majority of disease-related mutations are point mutations in exons 2, 3 or 4 (with the highest number in exon 3) that results in single amino acid substitutions in CRD1, CRD2 or CRD3 of the ectodomain of the mature protein; a splice mutation in intron 3 has been described that results in the insertion of four amino acids in CRD2 [13] and an inframe deletion in exon 3 that removes one amino acid has been described [14]. In addition, a missense mutation in exon 6 encodes an amino acid substitution at the base of the ectodomain proximal to the transmembrane region [15]. Most other mutations that have been identified in the 5' untranslated region of TNFRSF1A, in exon 1 that encodes the leader sequence, or in introns 4-8, have not been associated with TRAPS-related disease.…”

Section: Clinical and Genetic Characterisation Of Trapsmentioning

confidence: 96%

TNF and TNF Receptors in TRAPS

Todd¹,

Tighe²,

Powell³

2005

CMCAIAA

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Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is a hereditary auto-inflammatory periodic fever syndrome associated with autosomal dominant ectodomain mutations in the 55kDa tumor necrosis factor receptor (TNFRSF1A). Over forty mutations in TNFRSF1A are associated with TRAPS. Plasma levels of soluble TNFRSF1A (sTNFRSF1A) are abnormally low in TRAPS patients, as is shedding of TNFRSF1A by some patients' leucocytes. It was hypothesised that a deficit in neutralisation of TNF by sTNFRSF1A in TRAPS might result in an increased sensitivity to the inflammatory effects of TNF. However, not all TRAPS-related TNFRSF1A mutations result in defective receptor shedding by leucocytes. We found that dermal fibroblasts, but not leucocytes, from TRAPS patients with C33Y mutation demonstrated reduced shedding of TNFRSF1A, and that shedding of both wild-type and mutant truncated TNFRSF1A from transfected cell lines was similar. It is unlikely that a defect in TNFRSF1A shedding fully explains the clinical features of TRAPS. We investigated the behaviour of TRAPS-related TNFRSF1A mutants compared with wildtype in transfected cell lines: the mutant forms of TNFRSF1A retained signalling functions, but showed abnormalities of intra-cellular trafficking and TNF binding suggestive of protein misfolding. The severity of the abnormalities were observed with different mutants correlated with the degree of penetrance and clinical severity. We hypothesise that aggregation and ligand-independent signalling of mutant TNFRSF1A may occur. The increased understanding of the genetic basis and pathophysiology of TRAPS has facilitated therapeutic advances in the clinical management of this condition, particularly the use of the TNF-neutralising agent etanercept.

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Section: Clinical and Genetic Characterisation Of Trapsmentioning

confidence: 96%

TNF and TNF Receptors in TRAPS

Todd¹,

Tighe²,

Powell³

2005

CMCAIAA

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“…R92Q, a TNFRSF1A variant encoded by exon 4, is found in 1–2.5% of the normal population and presents with an incomplete penetrance and milder or TRAPS-atypical clinical features 6 – 9. To date, only two mutations have been reported in exon 6: ( a ) I170N/p.Ile199Asn,10 an amino acid substitution very close to the TNFRSF1A cleavage site (between p.Asn201 and p.Val202), which is adjacent to the transmembrane domain of TNFRSF1A11 12 and ( b ) L167_G175del/p.Leu196_Gly204del,9 the first large in-frame interstitial deletion.…”

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confidence: 99%

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

Stojanov

Dejaco

Lohse

et al. 2007

Annals of the Rheumatic Diseases

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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 TNFa in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS.

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“…These mutations have higher penetrance of phenotype [54]. Some mutations such as R92Q and P46L have very low penetrance but there is some evidence that they may play a role in various inflammatory rheumatic diseases [53,58,59]. MWS is characterized by recurrent episodes of urticaria, fever and polyarthralgia.…”

Section: Tumor Necrosis Factor Receptor-associated Periodic Syndrome mentioning

confidence: 97%

Molecular and Genetic Characteristics of Hereditary Autoinflammatory Diseases

Tunca¹,

Özdoğan

2005

CDTIA

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Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

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Tumor necrosis factor receptor–associated periodic syndrome characterized by a mutation affecting the cleavage site of the receptor: Implications for pathogenesis

Cited by 42 publications

References 7 publications

TNF and TNF Receptors in TRAPS

TNF and TNF Receptors in TRAPS

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

Molecular and Genetic Characteristics of Hereditary Autoinflammatory Diseases

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