Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation

Ding Chen; Tao Xu; Mengjun Tu; Jinlin Xu; Chenchen Zhou; Lulu Cheng; Ruqing Yang; Tanchu Yang; Weiwei Zheng; Xiubin He; Ruzhi Deng; Xianglian Ge; Jin Li; Zongming Song; Junzhao Zhao; Feng Gu

doi:10.3389/fnmol.2017.00453

Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation

Front Mol Neurosci. 2018 Jan 12:10:453. doi: 10.3389/fnmol.2017.00453. eCollection 2017.

Authors

Ding Chen^{1

2}, Tao Xu^{1

2}, Mengjun Tu^{1

2}, Jinlin Xu^{1

2}, Chenchen Zhou^{1

2}, Lulu Cheng^{1

2}, Ruqing Yang³, Tanchu Yang³, Weiwei Zheng^{1

2}, Xiubin He^{1

2}, Ruzhi Deng^{1

2}, Xianglian Ge^{1

2}, Jin Li^{1

2}, Zongming Song^{1

2

4}, Junzhao Zhao³, Feng Gu^{1

2}

Affiliations

¹ State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
² Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China.
³ The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Department of Ophthalmology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.

Abstract

X-linked juvenile retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding retinoschisin (RS1), which leads to a significant proportion of visual impairment and blindness. To develop personalized genome editing based gene therapy, knock-in animal disease models that have the exact mutation identified in the patients is extremely crucial, and that the way which genome editing in knock-in animals could be easily transferred to the patients. Here we recruited a family diagnosed with XLRS and identified the causative mutation (RS1, p.Y65X), then a knock-in mouse model harboring this disease-causative mutation was generated via TALEN (transcription activator-like effector nucleases). We found that the b-wave amplitude of the ERG of the RS1-KI mice was significantly decreased. Moreover, we observed that the structure of retina in RS1-KI mice has become disordered, including the disarray of inner nuclear layer and outer nuclear layer, chaos of outer plexiform layer, decreased inner segments of photoreceptor and the loss of outer segments. The novel knock-in mice (RS1-KI) harboring patient-specific mutation will be valuable for development of treatment via genome editing mediated gene correction.

Keywords: X-linked juvenile retinoschisis; disease model; genome editing technologies; knock-in; mice; retina.