title: Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.
abstract: Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, UK.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Pink
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.forename: Venu
authors.initials: V
authors.lastname: Pullabhatla
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Spain
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.forename: A David
authors.initials: AD
authors.lastname: Burden
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology; D017422:Sequence Analysis, DNA
chemical_list: C122187:IL36RN protein, human; D007378:Interleukins