Autosomal Recessive RDH12-Leber Congenital Amaurosis Retinal Organoids Suggest Phospholipid Pathway Dysregulation
5 affiliations
- 1Development, Ageing and Disease, UCL Institute of Ophthalmology, London EC1V 9EL, UK
- 2Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1AT, UK
- 3Electron Microscopy Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
- 4Department of Genetics, Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK
- 5Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
Abstract
NADPH-dependent retinol dehydrogenase 12 (RDH12) reduces all-trans-retinal in photoreceptor inner segments to regulate the phototransduction cascade and control the concentration of retinoids in the retina. Variants in RDH12 have been reported to cause an array of retinal disease phenotypes, including autosomal recessive (AR) Leber congenital amaurosis (LCA), a severe form of childhood blindness, and autosomal dominant (AD) retinitis pigmentosa (RP), a milder late-onset rod-dominant disease. Animal models have failed to recapitulate the clinical phenotype; hence, we generated human induced pluripotent stem cell (hiPSC) derived retinal organoids (RO) from a patient with homozygous missense variant c.619A>G p.(Asn207Asp) in RDH12 (RDH12-AR), a patient with heterozygous c.759del p.(Phe254Leufs*24) (RDH12-AD), and an unaffected control. RDH12-AR ROs develop shortened rod and cone photoreceptors (from the outer limiting membrane to the tip of the outer segment), which lack RDH12 localisation in the inner segment. Bulk transcriptomic analysis revealed cone marker and apoptosis dysregulation in RDH12-AR ROs compared to unaffected controls, but phospholipid transport is perturbed in RDH12-AR ROs compared to RDH12-AD. Our study helps to decipher the distinct disease pathways involved in RDH12 retinopathies; however, further modelling from additional patients with isogenic controls will strengthen the findings and aid identification of targets for therapeutic approaches.
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BibTeX
@article{mejecase2026autosomal,
title = {{Autosomal Recessive RDH12-Leber Congenital Amaurosis Retinal Organoids Suggest Phospholipid Pathway Dysregulation}},
author = {Cécile Méjécase and Lyes Toualbi and Ya Zhou and Riccardo Cheloni and Neelima Nair and Nicholas Owen and Hajrah Sarkar and Jieren Bornia and Maria Toms and Pablo Soro-Barrio and Mariya Moosajee},
journal = {International journal of molecular sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198880},
url = {https://europepmc.org/article/PMC/PMC13665329},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autosomal Recessive RDH12-Leber Congenital Amaurosis Retinal Organoids Suggest Phospholipid Pathway Dysregulation
AU - Cécile Méjécase
AU - Lyes Toualbi
AU - Ya Zhou
AU - Riccardo Cheloni
AU - Neelima Nair
AU - Nicholas Owen
AU - Hajrah Sarkar
AU - Jieren Bornia
AU - Maria Toms
AU - Pablo Soro-Barrio
AU - Mariya Moosajee
PY - 2026
DA - 2026/10/01
JO - International journal of molecular sciences
DO - 10.3390/ijms27198880
UR - https://europepmc.org/article/PMC/PMC13665329
AB - NADPH-dependent retinol dehydrogenase 12 (RDH12) reduces all-trans-retinal in photoreceptor inner segments to regulate the phototransduction cascade and control the concentration of retinoids in the retina. Variants in RDH12 have been reported to cause an array of retinal disease phenotypes, including autosomal recessive (AR) Leber congenital amaurosis (LCA), a severe form of childhood blindness, and autosomal dominant (AD) retinitis pigmentosa (RP), a milder late-onset rod-dominant disease. Animal models have failed to recapitulate the clinical phenotype; hence, we generated human induced pluripotent stem cell (hiPSC) derived retinal organoids (RO) from a patient with homozygous missense variant c.619A>G p.(Asn207Asp) in RDH12 (RDH12-AR), a patient with heterozygous c.759del p.(Phe254Leufs*24) (RDH12-AD), and an unaffected control. RDH12-AR ROs develop shortened rod and cone photoreceptors (from the outer limiting membrane to the tip of the outer segment), which lack RDH12 localisation in the inner segment. Bulk transcriptomic analysis revealed cone marker and apoptosis dysregulation in RDH12-AR ROs compared to unaffected controls, but phospholipid transport is perturbed in RDH12-AR ROs compared to RDH12-AD. Our study helps to decipher the distinct disease pathways involved in RDH12 retinopathies; however, further modelling from additional patients with isogenic controls will strengthen the findings and aid identification of targets for therapeutic approaches.
SN - 1422-0067
ER -