Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome.
Exp Dermatol
; 28(10): 1114-1117, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-28603914
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Skin Diseases, Vesiculobullous
/
Interleukins
/
Point Mutation
/
Mutation, Missense
/
Loss of Function Mutation
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Child
/
Female
/
Humans
/
Infant
/
Male
Language:
En
Journal:
Exp Dermatol
Journal subject:
DERMATOLOGIA
Year:
2019
Type:
Article
Affiliation country:
France