The canonical Wnt/β-catenin signaling pathway has been shown to play a major role during embryonic development and maturation of the central nervous system including the retina. It has a significant impact on retinal...The canonical Wnt/β-catenin signaling pathway has been shown to play a major role during embryonic development and maturation of the central nervous system including the retina. It has a significant impact on retinal vessel formation and maturation, as well as on the establishment of synaptic structures and neuronal function in the central nervous system. Mutations in components of the Wnt/β-catenin signaling cascade may lead to severe retinal diseases, while dysregulation of Wnt signaling can contribute to disease progression. Apart from the angiogenic role of Wnt/β-catenin signaling, research in the last decades leads to the theory of a protective effect of Wnt/β-catenin signaling on damaged neurons. In this review, we focus on the neuroprotective properties of the Wnt/β-catenin pathway as well as its downstream signaling in the retina.展开更多
Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pat...Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pathway.This study aimed to identify and functionally characterize novel FZD4 variants in patients with FEVR.Methods:Genetic sequencing of FZD4 was performed in a cohort of FEVR families,leading to the identification of five novel variants:c.434G>A,c.610T>G,c.844T>C,c.277C>T,and c.1155delC.Bioinformatic predictions,comprehensive clinical evaluations,and dual-luciferase reporter assays were conducted to assess the functional impact and pathogenicity of these variants.Results:All five FZD4 variants were found to significantly reduceβ-catenin signaling activity compared to wild-type FZD4.Among them,two variants previously classified as variants of uncertain significance(VUS)demon-strated functional impairment and clinical segregation consistent with pathogenicity,supporting their reclassi-fication as disease-causing mutations.Conclusions:These findings expand the known mutational spectrum of FZD4 in FEVR and highlight the critical role of functional validation in the interpretation of novel and uncertain variants.Incorporating experimental assays can improve diagnostic accuracy and inform clinical genetic counseling.展开更多
基金supported by the Deutsche Forschungsgemeinschaft(OH 214/4-3,FOR 1075,TP7)。
文摘The canonical Wnt/β-catenin signaling pathway has been shown to play a major role during embryonic development and maturation of the central nervous system including the retina. It has a significant impact on retinal vessel formation and maturation, as well as on the establishment of synaptic structures and neuronal function in the central nervous system. Mutations in components of the Wnt/β-catenin signaling cascade may lead to severe retinal diseases, while dysregulation of Wnt signaling can contribute to disease progression. Apart from the angiogenic role of Wnt/β-catenin signaling, research in the last decades leads to the theory of a protective effect of Wnt/β-catenin signaling on damaged neurons. In this review, we focus on the neuroprotective properties of the Wnt/β-catenin pathway as well as its downstream signaling in the retina.
基金supported by the National Natural Science Foundation of China(82271092).
文摘Purpose:Familial exudative vitreoretinopathy(FEVR)is a genetically heterogeneous retinal vascular disorder,with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pathway.This study aimed to identify and functionally characterize novel FZD4 variants in patients with FEVR.Methods:Genetic sequencing of FZD4 was performed in a cohort of FEVR families,leading to the identification of five novel variants:c.434G>A,c.610T>G,c.844T>C,c.277C>T,and c.1155delC.Bioinformatic predictions,comprehensive clinical evaluations,and dual-luciferase reporter assays were conducted to assess the functional impact and pathogenicity of these variants.Results:All five FZD4 variants were found to significantly reduceβ-catenin signaling activity compared to wild-type FZD4.Among them,two variants previously classified as variants of uncertain significance(VUS)demon-strated functional impairment and clinical segregation consistent with pathogenicity,supporting their reclassi-fication as disease-causing mutations.Conclusions:These findings expand the known mutational spectrum of FZD4 in FEVR and highlight the critical role of functional validation in the interpretation of novel and uncertain variants.Incorporating experimental assays can improve diagnostic accuracy and inform clinical genetic counseling.
