Mutations in the DSC2 gene cause Arrhythmogenic Right Ventricular Dysplasia (ARVD). The mechanisms by which these mutations confer histologic substrate remain unknown. It has been suggested that endogenous caspase-1 activity promotes the magnitude of the inflammatory response.

Fragments of cardiac tissue from 2 patients were collected after macroscopic and histopathological examination the patients’ hearts. A 63-year-old patient with ARVD caused by a DSC2 mutation (p.Arg132Cys) underwent heart transplantation. The diseased heart genome-wide expression profiling was compared with that of a non-diseased donor heart. The retained genes of interest were listed and classified according to their biological functions using Ingenuity Pathways Analysis (Ingenuity Systems Inc., Mountain View, CA). RT-qPCR and Western Blot (WB) were used to confirmed genes of interest.

Transcriptomic and RT-PCR data first revealed a down-expression of DSC2 mRNA and an unexpected overexpression of DSC3 mRNA in the posterior right ventricle of the ARVC patient (Figure) In the ARVD heart, DSC3 was found to be cleaved. Prediction software revealed that this cleavage could be due to Caspase-1. We observed an overexpression of Casp1 and other elements of inflammasome (CARD16, NLRP3) in the posterior RV of the ARVC patient. A down-expression of DSG2, DSP and RyR2 was also documented. Biological pathways analysis identified a relationship of Casp1 with apoptosis (BCL2, FOS), fibrogenesis (Col3A1, Col4A1, Col4A2, mmP9) and adipogenesis (IGF1, ADIPOQ) in the ARVC heart.

These findings suggest that in ARVD patients with a DSC2 variant: 1) there is a switch DSC2/DSC3 2) endogenous caspase-1 activity, by cleaving DSC3, contributes to desmosome dysfunction.