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Identification of Novel FZD4 Mutations in Familial Exudative Vitreoretinopathy and Investigating the Pathogenic
Erkuan Dai1, Min Liu2,3, Shujin Li2,3
1Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Purpose:
The purpose of this study is to report five novel FZD4 mutations identified in familial exudative vitreoretinopathy (FEVR) and to analyze and summarize the pathogenic mechanisms of 34 of 96 reported missense mutations in FZD4.
Methods:
Five probands diagnosed with FEVR and their family members were enrolled in the study. Ocular examinations and targeted gene panel sequencing were conducted on all participants. Plasmids, each carrying 29 previously reported FZD4 missense mutations and five novel mutations, were constructed based on the selection of mutations from each domain of FZD4. These plasmids were used to investigate the effects of mutations on protein expression levels, Norrin/β-catenin activation capacity, membrane localization, norrin binding ability, and DVL2 recruitment ability in HEK293T, HEK293STF, and HeLa cells.
Results:
All five novel mutations (S91F, V103E, C145S, E160K, C377F) responsible for FEVR were found to compromise Norrin/β-catenin activation of FZD4 protein. After reviewing a total of 34 reported missense mutations, we categorized all mutations based on their functional changes: signal peptide mutations, cysteine mutations affecting disulfide bonds, extracellular domain mutations influencing norrin binding, transmembrane domain (TM) 1 and TM7 mutations impacting membrane localization, and intracellular domain mutations affecting DVL2 recruitment.
Conclusions:
We expanded the spectrum of FZD4 mutations relevant to FEVR and experimentally demonstrated that missense mutations in FZD4 can be classified into five categories based on different functional changes.
Insights
Five novel FZD4 mutations were identified in familial exudative vitreoretinopathy (FEVR). These FZD4 mutations compromise Norrin/β-catenin activation, and missense mutations can be categorized by functional changes.
Area of Science:
- Genetics and Molecular Biology
- Ophthalmology
Background:
- Familial exudative vitreoretinopathy (FEVR) is a genetic disorder affecting retinal vasculature.
- Mutations in the FZD4 gene are a known cause of FEVR, impacting the Norrin signaling pathway.
Purpose of the Study:
- To identify and characterize novel FZD4 mutations in FEVR patients.
- To analyze the functional impact of previously reported and newly discovered FZD4 missense mutations.
Main Methods:
- Enrolled FEVR patients and family members for ocular examinations and genetic sequencing.
- Constructed plasmids with FZD4 mutations for in vitro functional assays.
- Assessed protein expression, Norrin/β-catenin activation, membrane localization, norrin binding, and DVL2 recruitment.
Main Results:
- Identified five novel FZD4 mutations (S91F, V103E, C145S, E160K, C377F) associated with FEVR.
- Demonstrated that these novel mutations impair FZD4's Norrin/β-catenin activation.
- Classified 34 reported missense mutations into five categories based on functional disruption (signal peptide, cysteine, extracellular, transmembrane, intracellular domains).
Conclusions:
- Expanded the known spectrum of FZD4 mutations causing FEVR.
- Provided experimental evidence for classifying FZD4 missense mutations based on their distinct functional consequences.
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