A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family

Objective. To characterize both phenotypic (clinical features and magnetic resonance imaging [MRI] findings) and genotypic aspects of autosomal-domina nt recurrent fever, also known as tumor necrosis factor receptor (TNFR)-ass ociated periodic syndrome (TRAPS), in a French family and to investigate th e role of the mutated 55-kd tumor necrosis factor alpha (TNF alpha) recepto r (TNFR1) in the pathogenesis of the disease. Methods. The coding region of TNFR1 was sequenced in 2 individuals with TRA PS (the propositus and her grandfather) and in 3 clinically unaffected rela tives. Expression of soluble TNFR1 (sTNFR1) was investigated in 3 of the fa mily members carrying a C30S mutation in TNFR1, and was compared with the l evels of soluble TNFR2 (sTNFR2) by enzyme-linked immunosorbent assay. The m embrane TNFR1 expression was then compared with membrane TNFR2 levels at th e surface of peripheral blood mononuclear cells by flow cytometric analysis . The clinical heterogeneity in this French family was investigated by sear ching polymorphic variants in the TNF alpha promoter by DNA sequencing. Results. Both the disease course and the clinical presentation in the propo situs were highly indicative of TRAPS, MRT study of the segmental inflammat ory process in the limbs showed abnormal signals in the muscle and subcutan eous tissue without involvement of adjacent joints or fascia, A novel misse nse mutation, C30S, in the first extracellular N-terminal cysteine-rich dom ain (CRD1) of TNFR1 was characterized in the propositus, her affected grand father, and her clinically unaffected father. Expression of membrane TNFR1 at the surface of monocytes and polymorphonuclear leukocytes, as well as th e levels of sTNFR1 in serum when the disease was not active were not modifi ed in the 3 individuals carrying the TNFR1 C30S mutation. In contrast, duri ng attacks, sTNFR1 levels remained abnormally low, as compared with the lev els in unrelated patients with active adult-onset systemic Still's disease. The clinical heterogeneity could not be explained by a polymorphic variant in the TNF alpha promoter. Conclusion, TRAPS is a distinct clinical and radiologic disease entity that is responsible for recurrent fever and migratory cellulitis-like processes ,vith localized myositis, We have identified a novel TNFR1 mutation, C30S, that is located in the CRD1 domain in a French family affected by the disea se. This mutation seems to affect the level of sTNFR1, which did not increa se in the propositus during inflammatory attacks.