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A novel mutation of tumor necrosis factor receptor alpha type 1 associated with TRAPS and amyloidosis

The tumor necrosis factor (TNF)-receptor-associated periodic syndrome (TRAPS) consists of recurrent fever with myalgia, painful erythema, and conjunctivitis typically lasting more than a week, with wide temperature fluctuations [Williamson et al., 1982; Hull et al., 2002]. The syndrome (MIM#142680) results from missense mutations in the gene (TNFRSF1A), which codes for the TNF receptor superfamily 1 A, a 55-kDa cell trans-membrane receptor which mediates signaling of tumor necrosis factor a (TNF-a). Thirty-seven mutations of TNFRSF1A have been associated with TRAPS [Sarrauste de Menthiere et al., 2003]. Mutations of extracellular cysteine residues produce a higher penetrance of the syndrome and a higher risk of severe amyloidosis [Hull et al., 2002]. We report a novel mutation of an extracellular cysteine residue in TNFRSF1A, found in a 43-years old, white Italian female who was referred to our nephrology clinic because of nephrotic syndrome for which kidney biopsy revealed AA amyloidosis. Of note, at age 28 years, she developed a severe proliferative glomerulonephritis with acute renal failure requiring transient hemodialysis. A diagnosis of lupus erythematosus was retained, and she was successfully treated with intravenous cyclophosphamide and steroids. DNA analysis by direct sequencing of PCR-amplified exons 2, 3, 4, and 5 of TNFRSF1A showed a heterozygous G to A transition in codon 30 relative to the signal peptide cleavage site, resulting in the substitution of a tyrosine in place of a cysteine (C30Y). DNA analysis in the patient’s mother showed absence of the mutation. The father was not available for DNA sampling. Renal amyloidosis is the most serious long-term complication of TRAPS, leading to nephrotic syndrome and eventual renal failure. Amyloidosis occurs in 14% of TRAPS patients [Hull et al., 2002], but is more frequent with mutations of extracellular domain cysteines than with mutations affecting other residues of TNFRSF1A (amyloidosis in 24% vs. 2%, respectively) [Askentijevich et al., 2001]. The mutation found in our patient affects cysteine 30 that has already been found in other TRAPS patients to be mutated into serine (C30S) or arginine (C30R) [Hull et al., 2002]. In conclusion,we identified anewmutation ofTNFRSF1A in apatientwithTRAPSand renal amyloidosis.Whetherpatients with TNFRSF1A mutations are more prone to develop other autoimmune diseases with glomerulopathies deserves further attention.