Mutations in IL36RN/IL1F5 Are Associated with the Severe Episodic Inflammatory Skin Disease Known as Generalized Pustular Psoriasis

• Published in: American journal of human genetics Vol. 89; no. 3; pp. 432 - 437
• Main Authors: Onoufriadis, Alexandros, Simpson, Michael A., Pink, Andrew E., Di Meglio, Paola, Smith, Catherine H., Pullabhatla, Venu, Knight, Jo, Spain, Sarah L., Nestle, Frank O., Burden, A. David, Capon, Francesca, Trembath, Richard C., Barker, Jonathan N.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.09.2011; Cell Press; Elsevier
• Subjects: Biological and medical sciences; Bullous diseases of the skin; Child; Child, Preschool; Cytokines; Dermatology; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Predisposition to Disease - genetics; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunity, Innate - genetics; Immunity, Innate - immunology; Interleukins - genetics; Interleukins - immunology; Interleukins - metabolism; Male; Medical genetics; Medical sciences; Middle Aged; Models, Molecular; Molecular and cellular biology; Mutation; Mutation, Missense - genetics; Pedigree; Psoriasis; Psoriasis - genetics; Psoriasis - immunology; Sequence Analysis, DNA; Signal transduction; Human; Skin disease; Pustular psoriasis; Critically ill; Pustulosis dermatosis; Genetics; Mutation; Generalized; Inflammatory disease
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.07.022

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.