Résumé
Disorders of the primary cilium (ciliopathies) are characterized by genetic heterogeneity and highly variable clinical representation like Oral-Facial-Digital (OFD) syndrome. We recently detected mutations in a gene, CPH-RP, previously associated with OFD, in a patient presenting with an inherited retinal dystrophy, retinitis pigmentosa (RP). RP is characterized by progressive visual loss due to degeneration of the light-sensing photoreceptors and/or their underlying support tissue, the retinal pigment epithelium (RPE).To better understand the mechanism of RP appearance caused by the CPH-RP gene mutations, we generated induced pluripotent stem cells (iPSCs) from the RP patient and differentiated them into RPE and mature retinal organoids containing a layer of photoreceptors. Interestingly, we noted a defective formation of the primary cilium in the iPSC-derived RPE. The cilium was present in a higher number of patient cells than controls and was significantly longer. Furthermore, the tightly packed RPE shows signs of losing its tight junctions which indicates the triggering of partial Epithelial to Mesenchymal Transition (EMT). This in turn modified polarized VEGF and PEDF secretion. We thus focused on the connecting cilium of the photoreceptors, which is situated between the metabolic inner segments and light-sensing outer segments. The reduced levels of CPH-RP gene expression in iPSC-derived photoreceptors provoked alterations in the expression of canonical visual cycle proteins, such as ABCA4, normally located in the outer segments.Taken together, we have validated that CPH-RP can be a causative gene for RP and suggest that the disease mechanism could be due to abnormal cilium formation, which can affect RPE development and ciliary transport in the photoreceptors.