期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26939-9
关键词
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资金
- Campaign Urging Research for Eosinophilic Disease (CURED) [R37 AI045898, R01 AI124355, U19 AI070235, P30 DK078392]
- [K99/R00 AI158660]
By conducting whole-exome sequencing in multiple multiplex families, rare variants in desmosome-associated proteins DSP and PPL were found to be associated with eosinophilic esophagitis (EoE), affecting barrier integrity and cell motility in esophageal epithelial cells. Acquired loss of esophageal DSP and PPL was also observed in non-familial EoE patients.
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.
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