ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Stem Cell Research
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1511066
This article is part of the Research Topic Studying Rare Diseases Using induced Pluripotent Stem Cell (iPSC)-based Model Systems View all 4 articles
Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids
Provisionally accepted
Cécile Méjécase 1,2 Ya Zhou 3 Nicholas Owen 1 Pablo Soro-Barrio 4 Riccardo Cheloni 1,5 Neelima Nair 1 Hajrah Sarkar 1,2 Lyes Toualbi 1,2 Mariya Moosajee 1,2,5*- 1 Institute of Ophthalmology, Faculty of Brain Sciences, University College London, London, England, United Kingdom
- 2 Laboratory of Ocular Genomics and Therapeutics, Francis Crick Institute, London, England, United Kingdom
- 3 Electron Microscopy Science Technology Platform, Francis Crick Institute, London, United Kingdom
- 4 Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, London, United Kingdom
- 5 Moorfields Eye Hospital, NHS Foundation Trust, London, United Kingdom
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Retinal dehydrogenase 12 (RDH12) is a photoreceptor NADPH-dependent retinal reductase enzyme, converting all-trans-retinal to all-trans-retinol. Heterozygous variants in RDH12 cause a rare autosomal dominant (AD) retinitis pigmentosa. As no disease models exist, we generated human induced pluripotent stem cell derived retinal organoids (RO) from a RDH12-AD patient (with pathogenic variant c.759del, p.Phe254Leufs*24), alongside a healthy unaffected control. RDH12-AD RO exhibited correct localisation of RDH12 to the photoreceptor inner segments up to week 44, however, transmission electron microscopy at week 37 showed photoreceptors were less abundant and shorter in length. Visual cone function, retinol biosynthesis and the vitamin A pathway were also highly disrupted at week 44. Our study is the first to describe a RDH12-AD disease model with pathology at later stages of photoreceptor differentiation, in keeping with the milder disease course seen in humans. It provides insights into the aetiology and possible targets for future therapeutic development.
Keywords: RDH12, autosomal dominant, Retinitis Pigmentosa, retinal organoids, IPSC, Vitamin A
Received: 14 Oct 2024; Accepted: 31 Mar 2025.
Copyright: © 2025 Méjécase, Zhou, Owen, Soro-Barrio, Cheloni, Nair, Sarkar, Toualbi and Moosajee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Mariya Moosajee, Institute of Ophthalmology, Faculty of Brain Sciences, University College London, London, EC1V 9EL, England, United Kingdom
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