Abstract
Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the progressive loss of photoreceptors that currently lacks effective treatment. Here, we investigated the effects of the PRPF8-Y2334N variant on neural retina cells using human induced pluripotent stem cell (hiPSC)-derived retinal organoids. Expression of PRPF8-Y2334N variant resulted in photoreceptor defects, including thinning of the outer segment layer. This indicates that the neural retina is impacted independently of retinal pigment epithelium (RPE). At the molecular level, we observed relatively minor changes in mRNA expression in multiple retinal cells. We also found splicing alterations in genes associated with neural and retinal diseases, including those involved in intraflagellar transport, suggesting that these genes may represent common targets of splicing factor mutations. Finally, we detected the misexpression of several circular RNAs (circRNAs), which could serve as early biomarkers of splicing defects caused by RP mutations. Together, we present a model of RP that recapitulates photoreceptor degeneration and demonstrates that these defects are independent of RPE degeneration.
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Acknowledgement
We would like to thank Jana Machatová-Křížová and Naděžda Vaškovicová for technical assistance and Pvel Draber, Reinhard Lührmann, Pavel Tomancak and Karla Neugebauer for providing reagents.
Funding
This work was supported by Project JAC CZ.02.01.01/00/22_008/0004575 "RNA for therapy", co-funded by the European Union, Ministry of Health of the Czech Republic, (NU22-07-00380 to T.B.) and Charles University Grant Agency (1170920 to F.Z.). We also acknowledge the Light Microscopy Core Facility, IMG, supported by MEYS (LM2023050, CZ.02.1.01/0.0/0.0/18_046/0016045 and CZ.02.01.01/00/23_015/0008205), for image acquisition and analysis, and ELIXIR-CZ research infrastructure, funded by MEYS project LM2023055, for bioinformatics analysis.
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D. Staněk, Z. Cvačková, and F. Zimmann conceptualized experiments. D. Staněk, T. Bárta and M. Kolář acquired the funding. F. Zimmann, P. Banik, E. Hrubá, Z. Cvačková, T. Bárta performed the experiments. F. Zimmann, J. Kubovčiak, P. K. Thakur, M. Čapek, M. Kolář performed the analyses. R. Dobrovolný provided resources. The manuscript was written by F. Zimmann and D. Staněk.
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Zimmann, F., Banik, P., Kubovčiak, J. et al. PRPF8-associated retinitis pigmentosa variant induces human neural retina-autonomous photoreceptor defects. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40376-y
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DOI: https://doi.org/10.1038/s41598-026-40376-y
