Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis
Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis
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DOI：
10.1172/jci.insight.99922
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Rothenberg, Marc E.
中科院分区：
文献类型：
--
作者：
Sherrill, Joseph D.;Kiran, K. C.;Rothenberg, Marc E.
嗜酸性食管炎(EoE)是一种变态反应性炎症性食管炎，具有复杂的遗传病因，常与其他合并症相关。通过对63名EoE患者和60名未受影响的家系成员进行全外显子组测序(WES)和基于家系的TRIO分析，我们试图发现罕见的编码变异。WES分析确定了脱氢酶E1和转酮醇酶结构域1(DHTKD1)中5个罕见的、具有破坏性的变异。罕见的变异负荷分析显示，EoE中存在过多的可能具有破坏性的DHTKD1突变(P=0.01)。有趣的是，我们还在DHTKD1同源基因OGDHL中发现了7个变异体。利用shRNA转导的食道上皮细胞和/或患者成纤维细胞，我们进一步表明，正常的DHTKD1或OGDHL表达的中断会削弱线粒体的功能。最后，我们证明了DHTKD1表达的缺失增加了ROS的产生并诱导了Viperin的表达，该基因以前被证明参与了T细胞中Th2细胞因子的产生。在EoE患者的食道活检组织中，Viperin的表达较正常对照组增加，IL-13可上调其在食道上皮细胞中的表达。这些数据确定了一系列罕见的遗传变异，这些变异涉及DHTKD1和OGDHL在EoE的遗传病因中的作用，并强调了EoE线粒体功能障碍的潜在致病作用。
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.