Huang, Kang-ChiehWang, Mong-LienChen, Shih-JenKuo, Jean-ChengWang, Won-JingNguyen, Phan Nguyen NhiWahlin, Karl J.Lu, Jyh-FengTran, Audrey A.Shi, MichaelChien, YuehYarmishyn, Aliaksandr A.Tsai, Ping-HsingYang, Tien-ChunJane, Wann-NengChang, Chia-ChingPeng, Chi-HsienSchlaeger, Thorsten M.Chiou, Shih-Hwa2020-03-232020-03-232019-11-12Huang, K. C., Wang, M. L., Chen, S. J., Kuo, J. C., Wang, W. J., Nguyen, P. N. N., ... & Chien, Y. (2019). Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis. Stem cell reports, 13(5), 906-923. 10.1016/j.stemcr.2019.09.0102213-6711https://hdl.handle.net/1805/22400X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalRetinal degenerationX-linked juvenile retinoschisisRetinal organoidInduced pluripotent stem cellsRetinogenesisCRISPR/Cas9 gene editingRS1RetinoschisinArticle