Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome

Exp Dermatol. 2019 Oct;28(10):1114-1117. doi: 10.1111/exd.13387. Epub 2017 Oct 26.

Abstract

The identification of loss-of-function mutations of the IL36RN gene encoding the interleukin-36 receptor antagonist (IL-36Ra) in generalized pustular psoriasis (GPP) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N-terminal amino acid IL36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV2F) missense IL36RN mutation segregating in a family with three GPP-affected patients. The V2F mutation does not alter IL-36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL-36Ra mutant retains its first N-terminal methionine. These results provide the first in vivo demonstration that removal of N-terminal methionine of native IL-36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.

Keywords: IL-36RN; IL-36Ra processing; generalized pustular psoriasis; inflammation.

Publication types

  • Case Reports
  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • C-Reactive Protein / analysis
  • Child
  • Consanguinity
  • Female
  • HEK293 Cells
  • Humans
  • Infant
  • Interleukins / deficiency*
  • Interleukins / genetics
  • Interleukins / physiology
  • Loss of Function Mutation*
  • Male
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Point Mutation*
  • Skin Diseases, Vesiculobullous / genetics*
  • Skin Diseases, Vesiculobullous / pathology
  • Syndrome

Substances

  • IL36RN protein, human
  • Interleukins
  • C-Reactive Protein