Using iPS cells to uncover cilia protein function and model disease

Abstract

SummaryPrimary cilia are small, hair‐like protrusions on most cells and the photoreceptor outer segment is a highly specialised light sensing primary cilium. Retinitis pigmentosa 2 (RP2) is a cilia and basal body protein that is involved in regulating ciliary protein traffic. Mutations in the RP2 gene lead to a severe form of X‐linked RP. Patient‐derived induced pluripotent stem cells (iPSC) provide a potent new technology, which allows the directed differentiation of most cell types to model disease. Recent advances have included the differentiation of iPSC into retinal pigmented epithelium (RPE) cells and three‐dimensional optic cups, which are stratified and express photoreceptor progenitor cells. We have reprogrammed skin fibroblasts from an RP2 patient, carrying the most common RP2 stop mutation R120X, into iPSC and differentiated them into RPE cells, allowing us to study RP2 mutation disease mechanisms in vitro. Using translational read‐through drugs (PTC124 and G418) we have successfully restored full‐length, functional RP2 in these cells. Therefore, using iPSC to model disease in relevant cell types and tissues provides an important tool for the evaluation of potential therapies.