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ResearchIn-Press PreviewCell biologyInflammation Open Access | 10.1172/jci.insight.183554

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

Daniela Kugelmann,1 Alexander García-Ponce,1 Nadja Thielemann,2 Mariya Y. Radeva,1 Maresa Anders,1 Da Eun Kang,1 Christian Siadjeu,3 Natalie Burkard,4 Anja K.E. Horn,1 Jessica Neubauer,1 Matthias Hiermaier,1 Desalegn T. Egu,1 Christoph Schmitz,5 Oliver Kurzai,2 Katri S. Vuopala,6 Outi Kuismin,7 Nicolas Schlegel,4 and Jens Waschke1

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Kugelmann, D. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by García-Ponce, A. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Thielemann, N. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Radeva, M. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Anders, M. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Kang, D. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Siadjeu, C. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Burkard, N. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Horn, A. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Neubauer, J. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Hiermaier, M. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Egu, D. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Schmitz, C. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Kurzai, O. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Vuopala, K. in: PubMed | Google Scholar

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Kuismin, O. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Schlegel, N. in: PubMed | Google Scholar |

1Vegetative Anatomy, Institute of Anatomy, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany

2Institute for Hygiene and Microbiology, Julius-Maximilians University Wuerzburg, Wuerzburg, Germany

3Systematics, Biodiversity and Evolution of Plants, Faculty of Biology, Ludwig-Maximilians-Universität München, Munich, Germany

4Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany

5Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

6Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

7Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

Find articles by Waschke, J. in: PubMed | Google Scholar

Published November 10, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.183554.
Copyright © 2026, Kugelmann et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 10, 2026 - Version history
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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.

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