Autosomal Recessive RDH12-Leber Congenital Amaurosis Retinal Organoids Suggest Phospholipid Pathway Dysregulation

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.