Cincinnati Children’s Research Horizons: Two Genes Associated with Familial EoE

Researchers (first author Tetsuo Shodaand senior author Marc Rothenberg) at “Cincinnati Children’s have identified two rare gene variants associated with inherited forms of eosinophilic esophagitis (EoE) that may also play roles as acquired mutations among the larger population of people with non-familial EoE.”  

Citation of article: Shoda, T., Kaufman, K.M., Wen, T. et al. Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis. Nat Commun 12, 6795 (2021). https://doi.org/10.1038/s41467-021-26939-9

The findings regarding the genes desmoplakin (DSP) and periplakin (PPL) were published Nov. 23, 2021 in Nature Communications (Link to article: Desmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis). “The proteins generated by these genes are found in the epithelial layer of the esophagus amid structures called desmosomes that help bind cells together. These variants of DSP and PPL appear to weaken the epithelial barrier, making the tissue more prone to damage from inflammation-causing eosinophils.”

Methods: Using whole-genome sequencing, the researchers discovered the variants among five members of a family that had multiple generations of members with EoE.  The team tested another 61 families with familial EoE and found 13 having either the DSP or PPL variants.

Key Findings:

• The authors “estimate that these gene variants account for about 21% of patients with familial EoE”
• “A series of functional analyses using an organotypic-like ALI culture system demonstrated that modulating wild-type DSP and PPL expression in vitro was functionally sufficient to induce changes in epithelial integrity (e.g., acantholysis) and barrier impairment, processes that are dysregulated in EoE”
• “DSP and PPL loss occurs in non-familial EoE, substantiating that the pathway identified initially by rare familial EoE cases is broadly applicable to familial and non-familial EoE”

My take:

1. This article provides data showing that genetic alterations affecting the epithelial barrier are important in the pathophysiology of EoE.
2. Often EoE is compared to eczema. This finding of altered epithelial barrier is analogous to eczema where many cases are due to a mutation in a protein called filaggrin, which is important in reducing the gap between skin cells (related blog: Eczema Rarely Linked to Food Allergy).

Related blog posts:

• Expecting Change in EoE Treatment
• 4-14-4 Rule: More Biopsies Recommended for EoE
• 2020 Eosinophilic Guidelines (AGA)
• Eosinophilic Esophagitis -FAQs
• What Happens When Topical Steroids Are Stopped in EoE?
• Eosinophilic Esophagitis -Up to Date Dietary Management Review
• Predicting Response to Topical Steroids in EoE
• Diet and Stress in Pediatric Eosinophilic Esophagitis
• Useful information on EoE Dietary Therapies
• What is EoE?
• EoE Update 2018 (Dr. Seth Marcus)
• Updated Consensus Guidelines for Eosinophilic Esophagitis
• Is EoE More Frequent in Patients with IBD? (No)
• Increased Risk of Eosinophilic Esophagitis with Esophageal Atresia
• Best Approach for Identifying Eosinophilic Esophagitis