title: Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.
abstract: BACKGROUND
  Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis.
  
  
  METHODS
  We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function.
  
  
  RESULTS
  We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36-receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor-like 2 (interleukin-1 receptor-related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients.
  
  
  CONCLUSIONS
  Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.).
authors.affiliation: Department of Dermatology and the Laboratory of Immunology, Hedi Chaker Hospital, Sfax University, Sfax, Tunisia.
authors.forename: Slaheddine
authors.initials: S
authors.lastname: Marrakchi
authors.forename: Philippe
authors.initials: P
authors.lastname: Guigue
authors.forename: Blair R
authors.initials: BR
authors.lastname: Renshaw
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Pei
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fraitag
authors.forename: Jihen
authors.initials: J
authors.lastname: Zribi
authors.forename: Elodie
authors.initials: E
authors.lastname: Bal
authors.forename: Céline
authors.initials: C
authors.lastname: Cluzeau
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Towne
authors.forename: Jason
authors.initials: J
authors.lastname: Douangpanya
authors.forename: Christian
authors.initials: C
authors.lastname: Pons
authors.forename: Sourour
authors.initials: S
authors.lastname: Mansour
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.forename: Hafedh
authors.initials: H
authors.lastname: Makni
authors.forename: Nadia
authors.initials: N
authors.lastname: Mahfoudh
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Josué
authors.initials: J
authors.lastname: Feingold
authors.forename: Smail
authors.initials: S
authors.lastname: Hadj-Rabia
authors.forename: Michel
authors.initials: M
authors.lastname: Favre
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Genin
authors.forename: Mourad
authors.initials: M
authors.lastname: Sahbatou
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: John E
authors.initials: JE
authors.lastname: Sims
authors.forename: Hamida
authors.initials: H
authors.lastname: Turki
authors.forename: Hervé
authors.initials: H
authors.lastname: Bachelez
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
mesh_terms: D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011565:Psoriasis / Q000235:genetics*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D012872:Skin Diseases, Vesiculobullous; D014416:Tunisia
chemical_list: D007375:Interleukin-1; D018123:Receptors, Interleukin