Germline Mutations in the Extracellular Domains of the 55 kDa TNF Receptor, TNFR1, Define a Family of Dominantly Inherited Autoinflammatory Syndromes

Abstract

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

A monoallelic double mutation as a cause for TNF receptor-associated periodic fever syndrome

“…FMF is caused by mutations in the MEFV (for MEditerranean FeVer)-gene [3], HIDS by mutations in the mevalonate kinase (MVK)-gene [4], and TRAPS develops due to mutations in the Tumor Necrosis Factor Receptor Superfamily Member 1A (TNFRSF1A)-gene. The latter is encoding for the 55 kDa TNF receptor TNFRSF1A, an archetypal proinflammatory receptor and member of a large group of proteins with homology in their extracellular domain [5][6][7].…”

“…Hence, often affections remain unrecognized and undiagnosed for years. During the last decade molecular studies revealed important progresses for the understanding of HPFSs [7][8][9][10][11]. Recent advances in molecular techniques have led to the identification of mutations that occur in several genes and are the underlying causes for these syndromes.…”

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).…”

“…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). It has been hypothesized that some mutations would indirectly interfere with activation-induced cleavage (1,5), although this process occurs at Asn 201 -Val 202 close to the transmembrane region (7).…”

“…Defective shedding and reduced serum levels have been demonstrated in vitro (1,5). It has been hypothesized that some mutations would indirectly interfere with activation-induced cleavage (1,5), although this process occurs at Asn 201 -Val 202 close to the transmembrane region (7). The aminopeptidase regulator of TNFR1 shedding (ARTS-1) binds to the receptor at the same region and facilitates cleavage (8).…”