Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids

Cécile Méjécase; Ya Zhou; Nicholas Owen; Pablo Soro-Barrio; Riccardo Cheloni; Neelima Nair; Hajrah Sarkar; Lyes Toualbi; Mariya Moosajee

doi:10.3389/fcell.2025.1511066

Dominant RDH12-retinitis pigmentosa impairs photoreceptor development and implicates cone involvement in retinal organoids

Front Cell Dev Biol. 2025 Apr 29:13:1511066. doi: 10.3389/fcell.2025.1511066. eCollection 2025.

Authors

Cécile Méjécase^{1

2}, Ya Zhou³, Nicholas Owen¹, Pablo Soro-Barrio⁴, Riccardo Cheloni^{1

5}, Neelima Nair¹, Hajrah Sarkar^{1

2}, Lyes Toualbi^{1

2}, Mariya Moosajee^{1

2

5}

Affiliations

¹ Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom.
² Ocular Genomics and Therapeutics, The Francis Crick Institute, London, United Kingdom.
³ Electron Microscopy Science Technology Platform, The Francis Crick Institute, London, United Kingdom.
⁴ Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, London, United Kingdom.
⁵ Department of Genetics, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.

Abstract

Introduction: 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.

Methods: As no disease models exist, we generated human induced pluripotent stem cell-derived retinal organoids (RO) from an RDH12-AD patient (with pathogenic variant c.759del, p.Phe254Leufs*24) alongside a healthy, unaffected control.

Results: RDH12-AD RO exhibited correct localization of RDH12 to the photoreceptor inner segments up to week 44; however, transmission electron microscopy at week 37 showed that 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.

Discussion: Our study is the first to describe an 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 etiology and possible targets for future therapeutic development.

Keywords: autosomal dominant; induced pluripotent stem cells; retinal dehydrogenase 12; retinal organoids; retinitis pigmentosa; vitamin A.