title: Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders.
abstract: OBJECTIVE
  Autoinflammatory disorders are caused by a primary dysfunction of the innate immune system. Among these disorders are hereditary recurrent fevers, which are characterized by recurrent episodes of fever and inflammatory manifestations affecting multiple tissues. Hereditary recurrent fevers often lack objective diagnostic criteria, thereby hampering the identification of disease-causing genes. This study was undertaken to identify a gene responsible for hereditary recurrent fevers.
  
  
  METHODS
  Copy number variations and point mutations were sought by array-comparative genomic hybridization and polymerase chain reaction sequencing, respectively. Serum cytokine levels were measured using Luminex technology. The effect of TNFRSF11A molecular defects on NF-κB signaling in cells expressing wild-type and mutated forms of the receptor was evaluated by luciferase assay.
  
  
  RESULTS
  A patient with multiple congenital anomalies and hereditary recurrent fever was found to carry a de novo heterozygous complex chromosomal rearrangement encompassing a duplication of TNFRSF11A, a gene known to regulate fever in rodents. We also identified a heterozygous frameshift mutation (p.Met416Cysfs*110) in TNFRSF11A in a mother and daughter with isolated hereditary recurrent fever. This mutation was associated with increased secretion of several inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-18 [IL-18], IL-1 receptor antagonist, interferon-γ) and altered the biologic effects of the receptor on NF-κB signaling. The disease in the patients described herein exhibits striking clinical similarities to TNF receptor-associated periodic syndrome, another hereditary recurrent fever involving a gene of the same family (TNFRSF1A).
  
  
  CONCLUSIONS
  The involvement of TNFRSF11A in hereditary recurrent fever highlights the key role of this receptor in innate immunity. The present results also suggest that TNFRSF11A screening could serve as a new diagnostic test for autoinflammatory disorders.
authors.affiliation: UMR S933, INSERM, Université Pierre et Marie Curie Paris 6, Hôpital Trousseau and AP-HP, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jéru
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cochet
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: Véronique
authors.initials: V
authors.lastname: Hentgen
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Mitjavila-Garcia
authors.forename: Shayan
authors.initials: S
authors.lastname: Sheykholeslami
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Le Borgne
authors.forename: Florence
authors.initials: F
authors.lastname: Dastot-Le Moal
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.forename: Sonia
authors.initials: S
authors.lastname: Karabina
authors.forename: Mathieu
authors.initials: M
authors.lastname: Mahevas
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lecron
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000328:Adult; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D005260:Female; D005838:Genotype; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics* / Q000378:metabolism
chemical_list: D053246:Receptor Activator of Nuclear Factor-kappa B