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

Abstract

Mutations in the extracellular domain of the 55-kD tumor-necrosis factor (TNF) receptor (TNFRSF1A), a key regulator of inflammation, define a periodic-fever syndrome, TRAPS (TNF receptor-associated periodic syndrome [MIM 142680]), which is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and/or conjunctivitis; some patients also develop systemic amyloidosis. Elsewhere we have described six disease-associated TNFRSF1A mutations, five of which disrupt extracellular cysteines involved in disulfide bonds; four other mutations have subsequently been reported. Among 150 additional patients with unexplained periodic fevers, we have identified four novel TNFRSF1A mutations (H22Y, C33G, S86P, and c.193-14 G-->A), one mutation (C30S) described by another group, and two substitutions (P46L and R92Q) present in approximately 1% of control chromosomes. The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, argue that these are low-penetrance mutations rather than benign polymorphisms. The c.193-14 G-->A mutation creates a splice-acceptor site upstream of exon 3, resulting in a transcript encoding four additional extracellular amino acids. T50M and c.193-14 G-->A occur at CpG hotspots, and haplotype analysis is consistent with recurrent mutations at these sites. In contrast, although R92Q also arises at a CpG motif, we identified a common founder chromosome in unrelated individuals with this substitution. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TRAPS and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations. In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes.

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: A low‐penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa

“…This condition is caused by mutations in exons 2-4 and 6 of the TNFRSF1A gene, which codes for the extracellular, soluble part of TNF receptor superfamily 1A (TNFRSF1A). Most common are the low-penetrance mutations P46L and R92Q, which were also present on ϳ1% of healthy control chromosomes in one study (12). One HIDS patient with 2 MVK mutations has been reported to carry in addition the TNFRSF1A P46L variant on 1 allele (13).…”

“…The patient's father was a healthy V377I heterozygote and showed a slightly depressed MK enzyme activity, while her mother 1956 STOJANOV ET AL was an asymptomatic carrier of the TNFRSF1A R92Q substitution. Generally, R92Q is regarded as a low-penetrance mutation associated with a broader range of symptoms than most TRAPS mutations and found especially in sporadic cases of TRAPS (12), although segregation with disease has been observed in 4 families (23). The R92Q allele frequency ranges from 1.8% (23) to 3.3% (12) in patients with clinical symptoms suggestive of TRAPS and amounts to ϳ1% in Irish and North American control populations (12).…”

“…Generally, R92Q is regarded as a low-penetrance mutation associated with a broader range of symptoms than most TRAPS mutations and found especially in sporadic cases of TRAPS (12), although segregation with disease has been observed in 4 families (23). The R92Q allele frequency ranges from 1.8% (23) to 3.3% (12) in patients with clinical symptoms suggestive of TRAPS and amounts to ϳ1% in Irish and North American control populations (12). Although an in vitro shedding defect is absent, soluble TNFRSF1A levels did not increase during an inflammatory episode in an R92Q carrier, suggesting that this amino acid substitution leads to an in vivo dysfunctional receptor (12).…”

“…The R92Q allele frequency ranges from 1.8% (23) to 3.3% (12) in patients with clinical symptoms suggestive of TRAPS and amounts to ϳ1% in Irish and North American control populations (12). Although an in vitro shedding defect is absent, soluble TNFRSF1A levels did not increase during an inflammatory episode in an R92Q carrier, suggesting that this amino acid substitution leads to an in vivo dysfunctional receptor (12). Thus, one could also speculate that our patient had TRAPS with the V377I mutation probably contributing to the symptoms.…”

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

“…142680) is a potentially lethal, autosomal-dominantly inherited autoinflammatory syndrome characterized by recurrent attacks of fever, skin lesions, and abdominal, joint, or muscle pain (1)(2)(3). To date ϳ20 mutations in the membrane-distal domains of TNFR superfamily 1A (TNFRSF1A) in patients with TRAPS have been reported (4)(5)(6). Defective shedding and reduced serum levels have been demonstrated in vitro (1,5).…”