Karolak Justyna A, Gambin Tomasz, Rydzanicz Malgorzata, Polakowski Piotr, Ploski Rafal, Szaflik Jacek P, Gajecka Marzena
Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.
Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
PeerJ. 2020 Apr 14;8:e8982. doi: 10.7717/peerj.8982. eCollection 2020.
Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in loss of visual acuity. The etiology of KTCN remains unclear. The purpose of this study was to assess the potential involvement of new genetic variants in KTCN etiology based on both the genomic and transcriptomic findings recognized in the same corneal tissues.
Corneal tissues derived from five unrelated Polish individuals with KTCN were examined using exome sequencing (ES), followed by enrichment analyses. For comparison purposes, the datasets comprising ES data of five randomly selected Polish individuals without ocular abnormalities and five Polish patients with high myopia were used. Expression levels of selected genes from the overrepresented pathways were obtained from the previous RNA-Seq study.
Exome capture discovered 117 potentially relevant variants that were further narrowed by gene overrepresentation analyses. In each of five patients, the assessment of functional interactions revealed rare (MAF ≤ 0.01) DNA variants in at least one gene from Wnt signaling (, , , , ) and focal adhesion (, , , , ) pathways. No genes involved in pathways enriched in KTCN corneas were overrepresented in our control sample sets.
The results of this first pilot ES profiling of human KTCN corneas emphasized that accumulation of sequence variants in several genes from Wnt signaling and/or focal adhesion pathways might cause the phenotypic effect and further points to a complex etiology of KTCN.
圆锥角膜（KTCN）是一种角膜突出变薄的疾病，可导致视力丧失。KTCN的病因尚不清楚。本研究的目的是基于在同一角膜组织中识别出的基因组和转录组学结果，评估新的基因变异在KTCN病因中的潜在作用。
对来自五名无亲缘关系的波兰圆锥角膜患者的角膜组织进行外显子组测序（ES），随后进行富集分析。为了进行比较，使用了包含五名随机选择的无眼部异常的波兰人和五名高度近视波兰患者的ES数据的数据集。从先前的RNA测序研究中获得了来自过度表达途径的选定基因的表达水平。
外显子捕获发现了117个潜在相关变异，通过基因过度表达分析进一步缩小范围。在五名患者中的每一名中，功能相互作用评估均显示，在Wnt信号通路（，，，，）和粘着斑（，，，，）途径的至少一个基因中存在罕见（MAF≤0.01）DNA变异。在我们的对照样本集中，KTCN角膜中富集的途径所涉及的基因没有过度表达。
对人类KTCN角膜进行的首次初步ES分析结果强调，Wnt信号通路和/或粘着斑途径中几个基因的序列变异积累可能导致表型效应，并进一步表明KTCN病因复杂。
