Dsg2 truncation causes a lethal barrier breakdown in mice
Inflammatory bowel diseases (IBD) such as Crohns disease (CD) have a complex aetiology with alterations of both the intestinal epithelial barrier and the IL23/IL17 immune response. Here, we investigated the role of a novel mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in the pathogenesis of IBD. DSG2 is known to regulate intestinal epithelial barrier integrity. Genetic analysis of a CD patient revealed a novel likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. We generated an enterocyte-specific mouse model, recapitulating the human mutation to study how the cytoplasmic truncation of Dsg2 affects intestinal barrier properties systemically. Moreover, we analysed the intestinal genetic profile in these mice and compared it to IBD patients. We describe a first CD patient with a rare mutation in the DSG2 gene causing cytoplasmic truncation with affects Dsg2 mobility. Mice with enterocyte-specific Dsg2 truncation suffered from a lethal intestinal barrier defect and presented a skewed IL17 response similar to CD patients. We identified the desmosomal cadherin Dsg2 as a regulator of the skewed IL17 response. These data indicate that desmosomes regulate inflammation similar to psoriasis which explains why the same novel immune therapies are effective for both diseases.