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

Onoufriadis, A. et al. (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. (doi: 10.1016/j.ajhg.2011.07.022)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1016/j.ajhg.2011.07.022

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 proinflamrnatory 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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burden, Professor David
Authors: Onoufriadis, A., Simpson, M.A., Pink, A.E., Di Meglio, P., Smith, C.H., Pullabhatla, V., Knight, J., Spain, S.L., Nestle, F.O., Burden, A.D., Capon, F., Trembath, R.C., and Barker, J.N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:American Journal of Human Genetics
Journal Abbr.:AJHG
ISSN:0002-9297
ISSN (Online):1537-6605

University Staff: Request a correction | Enlighten Editors: Update this record