Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis (2018)

hixxy · Apr 21, 2018

I thought some others might also find this interesting. I have EoE and my EoE and stomach problems flare from exertion and it's becoming pretty obvious it's playing quite a big role in my disease. I've also suspected that I have severe mitochondrial dysfunction in these organs but unable to prove it definitively.

JCI Insight. 2018 Apr 19;3(8). pii: 99922. doi: 10.1172/jci.insight.99922. [Epub ahead of print]

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

Sherrill JD, Kc K, Wang X, Wen T, Chamberlin A, Stucke EM, Collins MH, Abonia JP, Peng Y, Wu Q, Putnam PE, Dexheimer PJ, Aronow BJ, Kottyan LC, Kaufman KM, Harley JB, Huang T, Rothenberg ME.

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.

KEYWORDS:
Allergy; Cellular immune response; Immunology; Inflammation; Mitochondria
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https://www.ncbi.nlm.nih.gov/pubmed/29669943

Samuel · Apr 21, 2018

interesting that it could be mitochondrial.

i have many esophagus issues, but don't know what causes them. i have been assuming that one was caused by a gastroscopy biopsy that did not heal [it started right after it], and most are caused by vagus nerve issues. but that could be wrong. are there good blood or urine tests?

hixxy · Apr 21, 2018

Samuel said: ↑

interesting that it could be mitochondrial.

i have many esophagus issues, but don't know what causes them. i have been assuming that one was caused by a gastroscopy biopsy that did not heal [it started right after it], and most are caused by vagus nerve issues. but that could be wrong. are there good blood or urine tests?
Click to expand...

For EoE? No. It's diagnosed via esophageal biopsy collected during endoscopy. I think it's pretty routine to test for EoE now but I could be wrong, maybe they only test if someone is symptomatic.

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Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis (2018)

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Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis (2018)

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