Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

Kang Chieh Huang, Mong Lien Wang, Shih Jen Chen, Jean Cheng Kuo, Won Jing Wang, Phan Nguyen Nhi Nguyen, Karl J. Wahlin, Jyh Feng Lu, Audrey A. Tran, Michael Shi, Yueh Chien, Aliaksandr A. Yarmishyn, Ping Hsing Tsai, Tien Chun Yang, Wann Neng Jane, Chia-Ching Chang, Chi Hsien Peng, Thorsten M. Schlaeger*, Shih Hwa Chiou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


X-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.
Original languageEnglish
Pages (from-to)906-923
Number of pages18
JournalStem Cell Reports
Issue number5
StatePublished - 12 Nov 2019


  • CRISPR/Cas9 gene editing
  • induced pluripotent stem cells
  • retinal degeneration
  • retinal organoid
  • retinogenesis
  • retinoschisin
  • RS1
  • X-linked juvenile retinoschisis


Dive into the research topics of 'Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis'. Together they form a unique fingerprint.

Cite this