Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes

Autosomal dominant periodic fever syndromes are characterized by unexplaine d episodes of fever and severe localized inflammation. In seven affected fa milies, we found six different missense mutations of the 55 kDa tumor necro sis 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 memb rane TNFR1 and diminished shedding of potentially antagonistic soluble rece ptor. TNFR1-associated periodic syndromes (TRAPS) establish an important cl ass of mutations in TNF receptors. Detailed analysis of one such mutation s uggests impaired cytokine receptor clearance as a novel mechanism of diseas e.