Frameshift variants in the C-terminal of CTNNB1 cause familial exudative vitreoretinopathy by AXIN1-mediated ubiquitin-proteasome degradation condensation

Yining Liu¹, Mu Yang², Lin Fan³, Yunqi He⁴, Erkuan Dai⁵, Min Liu⁴, Lei Jiang⁶, Zhenglin Yang⁷, Shujin Li⁸

Affiliations

¹ Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
² Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; Jinfeng Laboratory, Chongqing, China.
³ Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, China; The University of Chinese Academy of Sciences, Beijing, China.
⁴ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China.
⁵ Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: lei.jiang@wmu.edu.cn.
⁷ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; Jinfeng Laboratory, Chongqing, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan, China; The University of Chinese Academy of Sciences, Beijing, China. Electronic address: yangzhenglin@cashq.ac.cn.
⁸ Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics and Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China; Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; Jinfeng Laboratory, Chongqing, China. Electronic address: lishujin@uestc.edu.cn.

PMID: 38096938
DOI: 10.1016/j.ijbiomac.2023.128570

Abstract

The β-catenin has two intrinsically disordered regions in both C- and N-terminal domains that trigger the formation of phase-separated condensates. Variants in its C-terminus are associated with familial exudative vitreoretinopathy (FEVR), yet the pathogenesis and the role of these variants in inducing abnormal condensates, are unclear. In this study, we identified a novel heterozygous frameshift variant, c.2104-2105insCC (p.Gln703ProfsTer33), in CTNNB1 from a FEVR-affected family. This variant encodes an unstable truncated protein that was unable to activate Wnt signal transduction, which could be rescued by the inhibition of proteasome or phosphorylation. Further functional experiments revealed the propensity of the Gln703ProfsTer33 variant to form cytoplasmic condensates, exhibiting a lower turnover rate after fluorescent bleaching due to enhanced interaction with AXIN1. LiCl, which specifically blocks GSK3β-mediated phosphorylation, restored signal transduction, cell proliferation, and junctional integrity in primary human retinal microvascular endothelial cells over-expressed with Gln703ProfsTer33. Finally, experiments on two reported FEVR-associated mutations in the C-terminal domain of β-catenin exhibited several functional defects similar to the Gln703ProfsTer33. Together, our findings unravel that the C-terminal region of β-catenin is pivotal for the regulation of AXIN1/β-catenin interaction, acting as a switch to mediate nucleic and cytosolic condensates formation that is implicated in the pathogenesis of FEVR.

Keywords: Condensation; Familial exudative vitreoretinopathy (FEVR); β-Catenin (CTNNB1).

Int J Biol Macromol. 2024 Feb;258(Pt 1):128570.doi: 10.1016/j.ijbiomac.2023.128570. Epub 2023 Dec 12. (IF:8.2).

Frameshift variants in the C-terminal of CTNNB1 cause familial exudative vitreoretinopathy by AXIN1-mediated ubiquitin-proteasome degradation condensation

Abstract

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