Repeated Episodes of GPP Induced by Respiratory Infections Are Mediated by Loss-of-Function IFIH1

Generalized pustular psoriasis (GPP) is a severe and recurrent autoinflammatory disease that can be induced by a variety of factors. At present, its etiology and pathogenesis have not yet been fully elucidated. Upper respiratory tract infections are the main predisposing factor in children with GPP, and the MDA5 protein encoded by the IFIH1, functions as a key receptor for sensing upper respiratory tract viruses and may contribute to the induction of antiviral and immunological responses.

We performed whole-exome sequencing in 80 pediatric GPP patients and conducted rare variant association analyses against healthy controls. Structural and expression analyses of mutant MDA5 were performed to evaluate mechanistic consequences. Identified IFIH1 variants were functionally characterized using IFN-β luciferase reporter assays, circular dichroism spectroscopy, and protein stability assays.

We identified eight IFIH1 rare variants in 10 pediatric GPP patients, accounting for 12.5% of the total cohort. Association analyses revealed a significantly higher prevalence of rare variants of IFIH1 in GPP patients as compared to healthy controls. IFIH1 variation was found to cause structural changes or decreased expression of its encoded protein MDA5, the intrinsic stability of the mutant was lower than that of the wild-type IFIH1. Notably, functional assays demonstrated that these IFIH1 variants (6/8) substantially impaired the production of interferon beta (IFN-β).

This study suggests that loss-of-function variants in IFIH1 may be associated with the pathogenesis of recurrent episodes of GPP triggered by URTI. These findings offer a theoretical basis for the development of targeted etiological and pathogenetic preventive measures.