CTNND1 variants cause familial exudative vitreoretinopathy through Wnt/Cadherin axis

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder that can cause vision loss. The CTNND1 gene encodes a cellular adhesion protein p120-catenin (p120), which is essential for vascularization, yet the function of p120 in postnatal physiological angiogenesis remains unclear. Here, we applied whole-exome sequencing (WES) on 140 probands of FEVR families and identified three candidate variants in the human CTNND1 gene. We performed inducible deletion of Ctnnd1 in the postnatal mouse endothelial cells (ECs) and observed typical phenotypes of FEVR. Immunofluorescence of retina flat mounts also revealed immune responses, including reactive astrogliosis and microgliosis accompanied by abnormal Vegfa expression. Using an unbiased proteomics analysis in combination with in vivo or in vitro approaches, we propose that p120 is critical for the integrity of cadherin/catenin complex, and that p120 activates Wnt signaling activity by protecting β-catenin from Gsk3β-ubiquitin-guided degradation. Treatment of CTNND1-depleted HRECs with Gsk3β inhibitors LiCl or CHIR-99021 successfully enhanced cell proliferation by preventing β-catenin from degradation. Moreover, LiCl treatment increased vessel density in Ctnnd1-deficient mouse retinas. Functional analysis also revealed that variants in CTNND1 cause FEVR by compromising the expression of adherens junctions (AJs) and Wnt signaling activity. Additionally, genetic interactions between p120 and β-catenin or α-catenin revealed by double heterozygous deletion in mice further confirmed that p120 regulates vascular development through the Wnt/Cadherin axis. Together, we propose that CTNND1 is a novel candidate gene associated with FEVR, and that variants in CTNND1 can cause FEVR through the Wnt/Cadherin axis.