Résumé
Purpose : Ciliary dysfunctions cause disorders referred to as ciliopathies. To date, pathogenic variants in the ciliary gene, CPH-RP*, have been exclusively associated with the highly severe ciliopathy, oral-facial-digital syndrome (OFD). We identified four patients from three unrelated families carrying CPH-RP variants and presenting with retinitis pigmentosa (RP), an inherited retinal disease (IRD) leading to photoreceptor degeneration, but no signs of OFD.*name altered pending publicationMethods : To validate CPH-RP as a putative RP causative gene, we combined Xenopus in vivo approaches and human iPSC-derived retinal models.Results : Our data show that CPH-RP is expressed during retinal development and that it plays an important role in in retinal pigment epithelium (RPE) differentiation. Furthermore, we identify a novel role for CPH-RP in ciliogenesis of the RPE. We demonstrate elongated ciliary defects that result in disrupted apical tight junctions, loss of apical-basal polarity affecting functionality, and onset of an epithelial-mesenchymal transition-like phenotype. Finally, our data also suggest connecting cilium anomalies in photoreceptors of CPH-RP iPSC-derived retinal organoids.Conclusions : Overall, our data not only highlight a critical role for CPH-RP in the retina, but demonstrate that hypomorphic CPH-RP mutations lead to RP. We thus identify CPH-RP as a novel IRD causative gene.