Rare Pathogenic Variants in IL36RN Underlie a Spectrum of Psoriasis-Associated Pustular Phenotypes

Abstract

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Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

“…After the initial reports of missense mutations in IL36RN (the gene coding for IL-36Ra) leading to generalized pustular psoriasis (17,18), several other missense mutations have been identified (38)(39)(40)(41)(42)(43). Altogether, 11 missense mutations of nine different residues have been reported to date (Table I).…”

Psoriasis

“…IL-36Ra blocks the proinflammatory cytokines IL-36a/b/g; when IL36RN is mutated, IL-36 signaling is uncontrolled with enhanced production of further proinflammatory cytokines (Onoufriadis et al 2011). However, IL36RN mutations only occur in a minority of patients (Setta-Kaffetzi et al 2013), thus, more genes are likely involved. Interestingly, a de novo mutation in the epidermal NF-kB activator CARD14 (Jordan et al 2012b) has been described to underlay a sporadic case of severe GPP, suggesting that KCs dysfunction is likely to play a predominant role in this disease phenotype.…”

442 European consensus statement on phenotypes of pustular psoriasis

“…All rights reserved. [10].These disease alleles are found in both European and Asian populations, and account for approximately 25% of GPP [11], 20% of ACH and 2% of PPP cases [12]. The latter, however, is somewhat controversial, as some studies found no association at all with PPP [13].…”

“…Another gene involved in GPP, PPP and ACH is AP1S3 [21]. It encodes a subunit of the adaptor protein complex 1 (AP-1), which is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes.…”