TNFRSF1A – TNF receptor-associated periodic syndrome (TRAPS)

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by heterozygous mutations in the TNFRSF1A gene, encoding the 55-kDa TNF receptor 1 (TNFR1). Clinically, TRAPS manifests with recurrent episodes of fever, abdominal pain, arthralgia/myalgia and migratory rash, with attacks often lasting >5 days (PMID:11443543). Disease onset ranges from infancy to adulthood with variable expressivity, even within the same kindred. Pathogenic variants predominantly cluster in the first two cysteine-rich domains (CRD1/CRD2) of the extracellular receptor, disrupting disulfide bonds and receptor folding. The genetic and functional concordance across multiple studies establishes TNFRSF1A as the causative gene for TRAPS.

Genetic analyses reveal autosomal dominant inheritance with high penetrance for cysteine-disrupting mutations. Over 70 distinct TNFRSF1A variants have been reported in more than 200 probands across unrelated families, including 28 of 394 patients in a systematic cohort (PMID:12209523). Segregation analysis in the Finnish kindred documented 4 affected relatives carrying the F112I mutation (PMID:11953985). Low-penetrance alleles such as R92Q and P46L occur in ~1% of controls but are enriched in patient series, suggesting modifier roles rather than full pathogenicity (PMID:11443543).

The variant spectrum includes missense substitutions (e.g., c.658T>A (p.Phe220Ile)), splice-site insertions and short in-frame deletions, most frequently targeting conserved cysteines. Founder effects underlie recurrent alleles such as R92Q in Europeans, whereas T50M and c.193-14G>A arise at CpG hotspots with recurrent mutational events (PMID:11443543). Noncysteine mutations generally correlate with milder, late-onset phenotypes and a lower risk of amyloidosis.

Mechanistic studies demonstrate that cysteine mutants misfold and form aberrant disulfide-linked oligomers, resulting in endoplasmic reticulum retention and reduced cell-surface TNFR1 expression (PMID:16684962). Phorbol myristate acetate-induced ectodomain shedding is impaired in patient monocytes and fibroblasts, yielding low soluble TNFR1 levels during flares (PMID:15334481; PMID:11953985). Mutant receptors retain death-domain signaling but exhibit defective ligand binding and altered NF-κB activation, elucidating the inflammatory phenotype (PMID:15312137).

Although low-penetrance variants (R92Q, P46L) are found in healthy carriers and show incomplete segregation, their enrichment in periodic fever cohorts suggests a context-dependent modifier effect. Co-inheritance with other autoinflammatory gene variants may further modulate the TRAPS phenotype, highlighting genetic heterogeneity within periodic fever syndromes.

In conclusion, the definitive association between TNFRSF1A and TRAPS is supported by extensive genetic, segregation, and functional evidence. TNFRSF1A genotyping is critical for diagnosing unexplained periodic fevers, guiding targeted therapies (anti-TNF, anti-IL-1), and enabling family counselling. Early molecular diagnosis improves patient management, reduces amyloidosis risk, and informs reproductive decisions.

References

• American journal of human genetics • 2001 • The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers PMID:11443543
• Arthritis and rheumatism • 2002 • The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome PMID:12209523
• Arthritis and rheumatism • 2002 • A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal-dominant recurrent fever PMID:11953985
• Arthritis and rheumatism • 2004 • Shedding of mutant tumor necrosis factor receptor superfamily 1A associated with tumor necrosis factor receptor-associated periodic syndrome: differences between cell types PMID:15334481
• Blood • 2006 • Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS) PMID:16684962
• Immunology • 2004 • Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour PMID:15312137

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