Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic <i>Sdccag8</i> mutations

Zhi-Lin Ren; Hou-Bin Zhang; Lin Li; Zheng-Lin Yang; Li Jiang

doi:10.24272/j.issn.2095-8137.2021.387

Volume 43 Issue 3

May 2022

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Article Navigation > Zoological Research > 2022 > 43(3): 442-456

Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387

Citation:

Zhi-Lin Ren, Hou-Bin Zhang, Lin Li, Zheng-Lin Yang, Li Jiang. Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological Research, 2022, 43(3): 442-456. doi: 10.24272/j.issn.2095-8137.2021.387

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Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations

doi: 10.24272/j.issn.2095-8137.2021.387

Zhi-Lin Ren^{1, 2},
Hou-Bin Zhang^{1, 2, 3},
Lin Li^{1, 2, 3},
Zheng-Lin Yang^{1, 2, 3
,
,},
Li Jiang^{1, 2, 3
,
,}

1.
Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
2.
Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
3.
Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences, Chengdu, Sichuan 610072, China

Funds: This work was supported by the Natural Science Foundation of China (81670893, 82121003), Science and Technology Department of Sichuan Province (2021JDZH0031), and Chinese Academy of Medical Sciences (2019-I2M-5-032)

More Information

Corresponding author: E-mail: yangzhenglin@cashq.ac.cn; 2478639152@qq.com
Received Date: 2022-03-14
Accepted Date: 2022-04-21

Published Online: 2022-04-25

Publish Date: 2022-05-18

Abstract

Abstract

Mutations in serologically defined colon cancer autoantigen protein 8 (SDCCAG8) were first identified in retinal ciliopathy families a decade ago with unknown function. To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies in vivo, we employed CRISPR/Cas9-mediated homology-directed recombination (HDR) to generate two knock-in mouse models, Sdccag8^Y236X/Y236X and Sdccag8^{E451GfsX467/E451GfsX467}, which carry truncating mutations of the mouse Sdccag8, corresponding to mutations that cause Bardet-Biedl syndrome (BBS) and Senior-Løken syndrome (SLS) (c.696T>G p.Y232X and c.1339–1340insG p.E447GfsX463) in humans, respectively. The two mutant Sdccag8 knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy, cystic renal disorder, polydactyly, infertility, and growth retardation, with varied age of onset and severity depending on the hypomorphic strength of the Sdccag8 mutations. To the best of our knowledge, these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype. Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration. Impaired cilia were observed in the mutant photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts derived from the knock-in mouse embryos, suggesting that SDCCAG8 plays an essential role in ciliogenesis, and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.
- SDCCAG8,
- Primary cilia,
- Retinal ciliopathy,
- Bardet-Biedl syndrome (BBS),
- Senior-L&oslash,
- ken syndrome (SLS),
- Nephronophthisis (NPHP),
- Polydactyly

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References(49)

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