在小鼠模型中，Ovol2破坏挽救了Ppcd1角膜营养不良表型，并通过遗传背景进行了修饰
Ppcd1 corneal dystrophy phenotypes are rescued by Ovol2 disruption and modified by genetic background in a mouse model.
摘要(中文译文)
后部多形性角膜营养不良（PPCD）是一种罕见的眼部疾病，以遗传异质性（PPCD1-4）和表型异质性为特征。基因定位和体外实验提供证据表明，OVOL2启动子突变与人类PPCD1相关，可能通过OVOL2过表达发挥作用。近期一项旨在构建与诱导人类疾病的突变同源的定点突变的研究报告了有限的表型效应，提示当前的鼠类模型在开发治疗方法方面的应用可能有限。在此，我们提供证据表明，通过操控遗传背景，鼠类模型可以作为研究该疾病基因编辑疗法的稳健平台。为支持我们的观点，我们采用了一种小鼠模型，该模型因与人类PPCD1位点同线的区域发生染色体重排而表现出PPCD样表型。观察到疾病表现依赖于敏感的小鼠遗传背景（DBA/2J）后，我们进一步证明，Ovol2的遗传破坏可挽救PPCD表型，包括角膜内皮化生、虹膜角膜角闭塞、眼压升高和视网膜变性。这些结果支持Ovol2上调驱动人类和小鼠模型中PPCD1的模型。此外，对遗传背景的研究为测试新型治疗干预策略提供了机会，并为研究人类疾病的修饰因素及其治疗提供了证据支持。
Abstract
Posterior polymorphous corneal dystrophy (PPCD) is a rare ocular disorder characterized by both genetic (PPCD1-4) and phenotypic heterogeneity. Genetic mapping and in vitro experiments provide evidence that OVOL2 promoter mutations are associated with human PPCD1, possibly through OVOL2 overexpression. A recent effort to engineer point mutations orthologous to those that induce human disease reported limited phenotypic effects, suggesting that current murine models may be of limited use in developing therapeutic approaches. Here, we provide evidence that, by manipulating the genetic background, a murine model can serve as a robust platform for studying gene-editing therapies for this disease. To support our idea, we employed a mouse model that exhibits PPCD-like phenotypes resulting from a chromosomal rearrangement in a region syntenic to the human PPCD1 locus. Observing that disease presentation is dependent upon a sensitive murine genetic background (DBA/2J), we then demonstrated that genetic disruption of Ovol2 rescues PPCD phenotypes, including corneal endothelial metaplasia, iridocorneal angle occlusion, elevated intraocular pressure, and retinal degeneration. These results support the model that Ovol2 upregulation drives PPCD1 in both humans and the mouse model. Moreover, studies on the genetic background provide opportunities to test novel therapeutic intervention strategies and provide evidence to support investigations into modifiers of human disease and their treatment.
如何引用
AMA
Anna L Shen, Alex C Veith, C Dustin Rubinstein, Kathy J Krentz, Edward Glover, Susan A Moran, et al. Ppcd1 corneal dystrophy phenotypes are rescued by Ovol2 disruption and modified by genetic background in a mouse model.. Scientific reports. 2026; doi:10.1038/s41598-026-56664-6.
APA
Anna L Shen, Alex C Veith, C Dustin Rubinstein, Kathy J Krentz, Edward Glover, Susan A Moran, et al (2026). Ppcd1 corneal dystrophy phenotypes are rescued by Ovol2 disruption and modified by genetic background in a mouse model.. Scientific reports. https://doi.org/10.1038/s41598-026-56664-6
GB/T 7714
Anna L Shen, Alex C Veith, C Dustin Rubinstein, Kathy J Krentz, Edward Glover, Susan A Moran, et al. Ppcd1 corneal dystrophy phenotypes are rescued by Ovol2 disruption and modified by genetic background in a mouse model.[J]. Scientific reports, 2026 doi:10.1038/s41598-026-56664-6.
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