title: 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.
authors: Medical Unit, St. Bartholomew's and the Royal London Hospital School of Medicine and Dentistry, Whitechapel, London, England. m.f.mcdermott@mds.qmw.ac.uk
authors: M F
authors: MF
authors: McDermott
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authors: Aksentijevich
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authors: Galon
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authors: EM
authors: McDermott
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authors: Ogunkolade
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authors: Centola
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authors: Mansfield
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authors: Gadina
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authors: Pettersson
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mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D013577:Syndrome
chemical_list: D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I