Description:
<jats:sec><jats:label /><jats:p><jats:bold>Aims/Purpose:</jats:bold> Although EYS‐associated retinal disease is normally described as a photoreceptor dysfunction, the natural role of the EYS protein is not yet clearly defined and it may also affect the RPE, as has been previously shown for other genes causing retinal disease. We have studied the impact of <jats:italic>EYS</jats:italic> gene mutations on the maturation and function of an RPE cellular model obtained from a patient.</jats:p><jats:p><jats:bold>Methods:</jats:bold> RPE was differentiated in vitro from a patient‐derived iPSC line and characterized. Morphological assessment of EYS‐RPE included light microscopy and electron microscopy. We studied gene expression by rt qPCR and transcriptomic analysis and cellular localization of the main RPE markers by immunofluorescence. For physiology, we tested the transepithelial resistance, phagocytic activity and secretion of PEDF and VEGF.</jats:p><jats:p><jats:bold>Results:</jats:bold> Microscopic phenotyping of the EYS‐RPE shows areas where cells grow in several layers, different from the healthy RPE model that grows as a monostratified epithelium. Moreover, the ultrastructure shows a loose attachment between cells and a disorganized distribution of the organelles and vesicles compared to the polarized distribution inside a healthy RPE cell, among other differences. Regarding gene expression, several RPE markers are downregulated in the EYS‐RPE pointing to a general dysregulation of the RPE metabolism and differentiation. The immunofluorescence study correlates with the gene expression data. As expected from the previous information, the EYS‐RPE physiology is affected, including a diminished phagocytic capacity and altered secretion of PEDF and VEGF.</jats:p><jats:p><jats:bold>Conclusions:</jats:bold> Our data indicate that EYS dysfunction is not only a photoreceptor disease but also affects RPE at many levels, from differentiation to impairing some of its key roles in the retina, which may contribute to retinal disease in EYS patients.</jats:p></jats:sec>