PMID- 35361685
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20230224
IS  - 1468-6244 (Electronic)
IS  - 0022-2593 (Linking)
VI  - 60
IP  - 2
DP  - 2023 Feb
TI  - Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy.
PG  - 174-182
LID - 10.1136/jmedgenet-2021-108259 [doi]
AB  - 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/beta-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 beta-catenin that reduced 
      Norrin/beta-catenin signalling activity. Additionally, knockdown (KD) of CTNNB1 in 
      HRECs led to diminished mRNA levels of Norrin/beta-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/beta-catenin for FEVR and 
      expanded the causative variant spectrum of CTNNB1 for the prenatal diagnosis and 
      genetic counselling of FEVR.
CI  - (c) Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and 
      permissions. Published by BMJ.
FAU - He, Yunqi
AU  - He Y
AD  - Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, 
      China.
AD  - 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.
AD  - 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.
AD  - University of Chinese Academy of Sciences, Beijing, China.
FAU - Yang, Mu
AU  - Yang M
AD  - 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.
AD  - 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.
FAU - Zhao, Rulian
AU  - Zhao R
AD  - 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.
AD  - 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.
FAU - Peng, Li
AU  - Peng L
AD  - 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.
AD  - 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.
FAU - Dai, Erkuan
AU  - Dai E
AD  - Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Huang, Lulin
AU  - Huang L
AD  - 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.
AD  - 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.
FAU - Zhao, Peiquan
AU  - Zhao P
AD  - Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China zliny@yahoo.com lishujin91@126.com 
      zhaopeiquan@126.com.
FAU - Li, Shujin
AU  - Li S
AUID- ORCID: 0000-0002-7691-3776
AD  - 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 zliny@yahoo.com 
      lishujin91@126.com zhaopeiquan@126.com.
AD  - 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.
FAU - Yang, Zhenglin
AU  - Yang Z
AD  - Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, 
      China zliny@yahoo.com lishujin91@126.com zhaopeiquan@126.com.
AD  - 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.
AD  - 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.
AD  - University of Chinese Academy of Sciences, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220331
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (beta Catenin)
RN  - 0 (CTNNB1 protein, human)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Familial Exudative Vitreoretinopathies/genetics
MH  - *beta Catenin/genetics
MH  - Endothelial Cells
MH  - Retina
MH  - Phenotype
MH  - Mutation
MH  - Pedigree
MH  - DNA Mutational Analysis
MH  - *Retinal Diseases/genetics
OTO - NOTNLM
OT  - frameshift mutation
OT  - ophthalmology
COIS- Competing interests: None declared.
EDAT- 2022/04/02 06:00
MHDA- 2023/01/27 06:00
CRDT- 2022/04/01 05:35
PHST- 2021/10/07 00:00 [received]
PHST- 2022/03/12 00:00 [accepted]
PHST- 2022/04/02 06:00 [pubmed]
PHST- 2023/01/27 06:00 [medline]
PHST- 2022/04/01 05:35 [entrez]
AID - jmedgenet-2021-108259 [pii]
AID - 10.1136/jmedgenet-2021-108259 [doi]
PST - ppublish
SO  - J Med Genet. 2023 Feb;60(2):174-182. doi: 10.1136/jmedgenet-2021-108259. Epub 
      2022 Mar 31.