Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis

Tetsuo Shoda, Kenneth M. Kaufman, Ting Wen, Julie M. Caldwell, Garrett A. Osswald, Pathre Purnima, Nives Zimmermann, Margaret H. Collins, Kira Rehn, Heather Foote, Michael D. Eby, Wenying Zhang, Netali Ben-Baruch Morgenstern, Adina Y. Ballaban, Jeff E. Habel, Leah C. Kottyan, J. Pablo Abonia, Vincent A. Mukkada, Philip E. Putnam, Lisa J. Martin and Marc E. Rothenberg ()
Additional contact information
Tetsuo Shoda: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Kenneth M. Kaufman: Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center
Ting Wen: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Julie M. Caldwell: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Garrett A. Osswald: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Pathre Purnima: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Nives Zimmermann: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Margaret H. Collins: University of Cincinnati College of Medicine
Kira Rehn: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Heather Foote: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Michael D. Eby: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Wenying Zhang: University of Cincinnati College of Medicine
Netali Ben-Baruch Morgenstern: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Adina Y. Ballaban: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Jeff E. Habel: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Leah C. Kottyan: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
J. Pablo Abonia: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center
Vincent A. Mukkada: University of Cincinnati College of Medicine
Philip E. Putnam: University of Cincinnati College of Medicine
Lisa J. Martin: University of Cincinnati College of Medicine
Marc E. Rothenberg: Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Herein, we conduct whole-exome sequencing of a multigeneration EoE pedigree (discovery set) and 61 additional multiplex families with EoE (replication set). A series of rare, heterozygous, missense variants are identified in the genes encoding the desmosome-associated proteins DSP and PPL in 21% of the multiplex families. Esophageal biopsies from patients with these variants retain dilated intercellular spaces and decrease DSP and PPL expression even during disease remission. These variants affect barrier integrity, cell motility and RhoGTPase activity in esophageal epithelial cells and have increased susceptibility to calpain-14–mediated degradation. An acquired loss of esophageal DSP and PPL is present in non-familial EoE. Taken together, herein, we uncover a pathogenic role for desmosomal dysfunction in EoE, providing a deeper mechanistic understanding of tissue-specific allergic responses.

Date: 2021
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DOI: 10.1038/s41467-021-26939-9

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