Dsg2 truncation causes a severe intestinal epithelial barrier breakdown and alters microbiome and immune response.

Authors

Daniela Kugelmann, Alexander García-Ponce, Nadja Thielemann, Mariya Y Radeva, Maresa Anders, Da Eun Kang, Christian Siadjeu, Natalie Burkard, Anja Ke Horn, Jessica Neubauer, Matthias Hiermaier, Desalegn T Egu, Christoph Schmitz, Oliver Kurzai, Katri S Vuopala, Outi Kuismin, Nicolas Schlegel, Jens Waschke

Published in

JCI insight. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Inflammatory bowel diseases (IBD) including Crohn's disease (CD) are characterized by impaired intestinal epithelial barrier (IEB) function. Alterations in the desmosomal cadherin desmoglein 2 (Dsg2) have been linked to loss of IEB and intestinal inflammation in IBD. We investigated the pathogenic impact of a cytoplasmatic-truncating mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in an IBD patient. Genetic analysis of a CD patient revealed a likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. Generation of an enterocyte-specific mouse model to recapitulate the human mutation resulted in a lethal intestinal barrier defect which was evident in homozygous but not in heterozygous mice. In vitro, barrier defects correlated with changes in Dsg2 mobility and upregulation of pore-forming tight junction protein claudin-2. Organoids derived from heterozygous Dsg2 truncated mice exhibited increased epithelial susceptibility to proinflammatory cytokines. Bulk RNAseq followed by gene ontology analysis in homozygous mice revealed a skewed IL17/IL23 response overlapping with transcriptional changes in patients with CD. Furthermore, 16S rRNA sequencing revealed alterations in microbiome composition in animals that carried the Dsg2 truncation. In summary, a patient-derived mutation in the DSG2 gene causing cytoplasmic truncation in homozygous state induced a lethal intestinal barrier breakdown in mice paralleled by altered gut microbiota and intestinal immune response.

PMID:
43007723
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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