Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis

Onoufriadis, Alexandros and Simpson, Michael A. and Pink, Andrew E. and Di Meglio, Paola and Smith, Catherine H. and Pullabhatla, Venu and Knight, Jo and Spain, Sarah L. and Nestle, Frank O. and Burden, A. David and Capon, Francesca and Trembath, Richard C. and Barker, Jonathan N. W. N. (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. American Journal of Human Genetics, 89 (3). pp. 432-437. ISSN 0002-9297

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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.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Human Genetics
Additional Information:
Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2716
Subjects:
ID Code:
77888
Deposited By:
Deposited On:
22 Jan 2016 13:54
Refereed?:
Yes
Published?:
Published
Last Modified:
23 Sep 2020 02:34