LRP2 is a potential molecular target for pathological myopia

High myopia (HM) and posterior staphyloma (PS) are major causes of vision loss worldwide. Genetic and environmental factors, especially light exposure, contribute to myopia. Mutations in low-density lipoprotein-related receptor type 2, LRP2 cause syndromic myopia, and the Foxg1-Cre-Lrp2lox/lox mouse is a model for myopia and PS but the involvement of LRP2 in non-syndromic HM (NSHM) was unknown. We showed that LRP2 levels were decreased in the vitreous of 25 patients with NSHM and PS, and that in human donor eyes affected by PS, LRP2 expression was reduced in the neural retina and retinal pigment epithelium (RPE). The morphologic changes of these RPE were similar to those observed in the RPE of the Foxg1- Cre-Lrp2lox/lox mouse. In iPSc-derived human RPE cells (iRPE), LRP2 was expressed at a functional location, and LRP2 silencing by a specific siRNA regulated genes belonging to pathways involved in eye and neuronal development, visual perception, tissue remodeling, hormone metabolism and RPE structure, demonstrating that LRP2 orchestrates in RPE, functions that are essential for eye growth. Exposure of iRPE to light with LEDs of different wavelengths upregulated LRP2 expression, with higher efficacy for red light. Conversely, LRP2 expression was downregulated after cortisol exposure. Our findings link LRP2 to myopization and environmental factors and highlight its role in NSHM and PS in humans. LRP2 appears to be a viable target for interventional strategies in the treatment of NSHM. One Sentence SummaryLRP2, pivotal in the regulation of eye growth, exhibits a decrease in high myopic eyes. Its expression is augmented by light exposure in retinal pigment epithelial cells.