Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis.

Abstract

Eosinophilic esophagitis (EoE) is an allergic inflammatory esophageal disorder with a complex underlying genetic etiology often associated with other comorbidities. Using whole-exome sequencing (WES) of 63 patients with EoE and 60 unaffected family members and family-based trio analysis, we sought to uncover rare coding variants. WES analysis identified 5 rare, damaging variants in dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1). Rare variant burden analysis revealed an overabundance of putative, potentially damaging DHTKD1 mutations in EoE (P = 0.01). Interestingly, we also identified 7 variants in the DHTKD1 homolog oxoglutarate dehydrogenase-like (OGDHL). Using shRNA-transduced esophageal epithelial cells and/or patient fibroblasts, we further showed that disruption of normal DHTKD1 or OGDHL expression blunts mitochondrial function. Finally, we demonstrated that the loss of DHTKD1 expression increased ROS production and induced the expression of viperin, a gene previously shown to be involved in production of Th2 cytokines in T cells. Viperin had increased expression in esophageal biopsies of EoE patients compared with control individuals and was upregulated by IL-13 in esophageal epithelial cells. These data identify a series of rare genetic variants implicating DHTKD1 and OGDHL in the genetic etiology of EoE and underscore a potential pathogenic role for mitochondrial dysfunction in EoE.

• Authors: Joseph D Sherrill, Kiran Kc, Xinjian Wang, Ting Wen, Adam Chamberlin, Emily M Stucke, Margaret H Collins, J Pablo Abonia, Yanyan Peng, Qiang Wu, Philip E Putnam, Phillip J Dexheimer, Bruce J Aronow, Leah C Kottyan, Kenneth M Kaufman, John B Harley, Taosheng Huang, Marc E Rothenberg
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 8 (04 19 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 29669943 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• Interleukin-13
• Proteins
• RNA, Small Interfering
• Oxidoreductases
• Ketone Oxidoreductases
• DHTKD1 protein, human
• Ketoglutarate Dehydrogenase Complex
• Oxidoreductases Acting on CH-CH Group Donors
• RSAD2 protein, human

Topics

• Adult
• Child
• Cytokines (metabolism)
• Eosinophilic Esophagitis (congenital, etiology, immunology, pathology)
• Epithelial Cells (metabolism)
• Female
• Fibroblasts (metabolism)
• Humans
• Interleukin-13 (metabolism)
• Ketoglutarate Dehydrogenase Complex (metabolism)
• Ketone Oxidoreductases
• Male
• Mitochondria (metabolism, physiology)
• Mutation
• Oxidoreductases (genetics, metabolism)
• Oxidoreductases Acting on CH-CH Group Donors
• Proteins
• RNA, Small Interfering (genetics)
• T-Lymphocytes (metabolism)
• Up-Regulation (genetics)
• Exome Sequencing (methods)