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Original research
Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy
  1. Yunqi He1,2,3,4,
  2. Mu Yang2,3,
  3. Rulian Zhao2,3,
  4. Li Peng2,3,
  5. Erkuan Dai5,
  6. Lulin Huang2,3,
  7. Peiquan Zhao5,
  8. Shujin Li2,3,
  9. Zhenglin Yang1,2,3,4
  1. 1 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, China
  2. 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, the Department of Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
  3. 3 Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
  4. 4 University of Chinese Academy of Sciences, Beijing, China
  5. 5 Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
  1. Correspondence to Dr Zhenglin Yang, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China; zliny{at}; Dr Shujin Li, Sichuan Provincial People's Hospital, Chengdu, Sichuan, People's Republic of China; lishujin91{at}; Dr Peiquan Zhao, Xinhua Hospital, Shanghai, People's Republic of China; zhaopeiquan{at}


Background Familial exudative vitreoretinopathy (FEVR) is an inheritable blinding disorder with clinical and genetic heterogeneity. Heterozygous variants in the CTNNB1 gene have been reported to cause FEVR. However, the pathogenic basis of CTNNB1-associated FEVR has not been fully explored.

Methods Whole-exome sequencing was performed on the genomic DNA of probands. Dual-luciferase reporter assay, western blotting and co-immunoprecipitation were used to characterise the impacts of variants. Quantitative real-time PCR, EdU (5-ethynyl-2′-deoxyuridine) incorporation assay and immunocytochemistry were performed on the primary human retinal microvascular endothelial cells (HRECs) to investigate the effect of CTNNB1 depletion on the downstream genes involved in Norrin/β-catenin signalling, cell proliferation and junctional integrity, respectively. Transendothelial electrical resistance assay was applied to measure endothelial permeability. Heterozygous endothelial-specific Ctnnb1-knockout mouse mice were generated to verify FEVR-like phenotypes in the retina.

Results We identified two novel heterozygous variants (p.Leu103Ter and p.Val199LeufsTer11) and one previously reported heterozygous variant (p.His369ThrfsTer2) in the CTNNB1 gene. These variants caused truncation and degradation of β-catenin that reduced Norrin/β-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in HRECs led to diminished mRNA levels of Norrin/β-catenin targeted genes, reduced cell proliferation and compromised junctional integrity. The Cre-mediated heterozygous deletion of Ctnnb1 in mouse endothelial cells (ECs) resulted in FEVR-like phenotypes. Moreover, LiCl treatment partially rescued the defects in CTNNB1-KD HRECs and EC-specific Ctnnb1 heterozygous knockout mice.

Conclusion Our findings reinforced the current pathogenesis of Norrin/β-catenin for FEVR and expanded the causative variant spectrum of CTNNB1 for the prenatal diagnosis and genetic counselling of FEVR.

  • ophthalmology
  • frameshift mutation

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • YH and MY contributed equally.

  • Contributors ZY and SL designed the study. YH and MY conducted the experiments and prepared the original draft. ZY, SL and MY reviewed and edited the original draft. RZ and LP conducted the construction of plasmids and animal breeding. PZ and ED recruited the participants and made clinical diagnosis for the FEVR cases. LH performed the sequencing analysis. SL is responsible for the overall content.

  • Funding This study was supported by the National Natural Science Foundation of China (82101153 to MY, 82000913 to SL, 81790643 and 82121003 to ZY), the CAMS Innovation Fund for Medical Sciences (2019-12M-5-032), the Department of Science and Technology of Sichuan Province (2021YFS0369 and 2021JDGD0036 to ZY, 2022YFS0598 to SL) and the fund for Sichuan Provincial People’s Hospital (2021QN01 to MY).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.