title: Involvement of the same TNFR1 residue in mendelian and multifactorial inflammatory disorders.
abstract: OBJECTIVE
  TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92.
  
  
  METHODS
  TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1.
  
  
  RESULTS
  A TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p<5.10(-4)). It was associated with very high disease penetrance (0.9). Prediction of its impact on the protein structure revealed local conformational changes and alterations of the receptor electrostatic properties. R92W also impairs the TNFR1 expression at the cell surface and the levels of soluble receptor. Similar results were obtained with R92P, another mutation previously identified in a very small familial form with incomplete penetrance and variable expressivity. In contrast, TNFR1-R92Q behaves like the wild-type receptor.
  
  
  CONCLUSIONS
  These data demonstrate the pathogenicity of a mutation affecting arginine 92, a residue whose involvement in inflammatory disorders is deeply debated. Combined with previous reports on arginine 92 mutations, this study discloses an unusual situation in which different amino acid substitutions at the same position in the protein are associated with a clinical spectrum bridging Mendelian to multifactorial conditions.
authors.affiliation: UMR_S933, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. isabelle.jeru@trs.aphp.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jéru
authors.forename: Serge
authors.initials: S
authors.lastname: Charmion
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cochet
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Maria Teresa Mitjavila
authors.initials: MT
authors.lastname: Garcia
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Borgne
authors.forename: Pascal
authors.initials: P
authors.lastname: Cathebras
authors.forename: Jacques
authors.initials: J
authors.lastname: Gaillat
authors.forename: Sonia
authors.initials: S
authors.lastname: Karabina
authors.forename: Catherine
authors.initials: C
authors.lastname: Dodé
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Véronique
authors.initials: V
authors.lastname: Hentgen
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D015153:Blotting, Western; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D021381:Protein Transport; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity; D055815:Young Adult
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D001120:Arginine
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