Dataset Information

CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis.

ABSTRACT: Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder that can cause vision loss. CTNND1 encodes a cellular adhesion protein p120-catenin (p120), which is essential for vascularization with unclear function in postnatal physiological angiogenesis. Here, we applied whole-exome sequencing to 140 probands of FEVR families and identified 3 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 with reactive gliosis. Using unbiased proteomics analysis combined with experimental approaches, we conclude that p120 is critical for the integrity of adherens junctions (AJs) and that p120 activates Wnt signaling activity by protecting β-catenin from glycogen synthase kinase 3 beta-ubiqutin-guided (Gsk3β-ubiquitin-guided) degradation. Treatment of CTNND1-depleted human retinal microvascular ECs with Gsk3β inhibitors LiCl or CHIR-99021 enhanced cell proliferation. Moreover, LiCl treatment increased vessel density in Ctnnd1-deficient mouse retinas. Variants in CTNND1 caused FEVR by compromising the expression of AJs and Wnt signaling activity. Genetic interactions between p120 and β-catenin or α-catenin revealed by double-heterozygous deletion in mice showed that p120 regulates vascular development through the Wnt/cadherin axis. In conclusion, variants in CTNND1 can cause FEVR through the Wnt/cadherin axis.

SUBMITTER: Yang M

PROVIDER: S-EPMC9431724 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis.

Yang Mu M Li Shujin S Huang Li L Zhao Rulian R Dai Erkuan E Jiang Xiaoyan X He Yunqi Y Lu Jinglin J Peng Li L Liu Wenjing W Zhang Zhaotian Z Jiang Dan D Zhang Yi Y Jiang Zhilin Z Yang Yeming Y Zhao Peiquan P Zhu Xianjun X Ding Xiaoyan X Yang Zhenglin Z

JCI insight 20220722 14

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder that can cause vision loss. CTNND1 encodes a cellular adhesion protein p120-catenin (p120), which is essential for vascularization with unclear function in postnatal physiological angiogenesis. Here, we applied whole-exome sequencing to 140 probands of FEVR families and identified 3 candidate variants in the human CTNND1 gene. We performed inducible deletion of Ctnnd1 in the postnatal mouse endothelial cells (ECs) and observed ...[more]

PMID: 35700046

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Project description:BackgroundFamilial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation.MethodsClinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease.ResultsA 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein.ConclusionsTwo novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Project description:PurposeTo expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease.Participants74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing.MethodsPanel-based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype-phenotype co-segregation analysis.Results40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR-causative genes. The etiological mutation detection rate was 37.74% (20/53) in family-attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early-onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence-onset subgroup (6-16 years old, 42.1%) and the late-onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort.ConclusionsWe systematically screened nine FEVR disease-associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.

Dataset Information

CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis.

Publications

CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis.

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