Abstract
SummaryLeber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in three-dimensional optic cups and retinal pigment epithelium (RPE) from iPSCs with this common CEP290 mutation to investigate disease mechanisms and evaluate candidate therapies. iPSCs differentiated normally into RPE and optic cups, despite abnormal CEP290 splicing and cilia defects. The highest levels of aberrant splicing and cilia defects were observed in optic cups, explaining the retinal-specific manifestation of this CEP290 mutation. Treating optic cups with an antisense morpholino effectively blocked aberrant splicing and restored expression of full-length CEP290, restoring normal cilia-based protein trafficking. These results provide a mechanistic understanding of the retina-specific phenotypes in CEP290 LCA patients and potential strategies for therapeutic intervention.
Highlights
Primary cilia are sensory organelles that project from the cell surface in most eukaryotic cells and affect signaling cascades in response to environmental stimuli
Degeneration of photoreceptors is a major cause of blindness, and Leber congenital amaurosis (LCA) is a recessively inherited form of retinal dystrophy resulting in severe visual loss in early childhood (Koenekoop, 2004)
LCA Fibroblasts Express Misspliced CEP290 and Have Impaired Ciliogenesis Fibroblasts were derived from a dermal skin biopsy of a 39-yearold male who was diagnosed with LCA as a child
Summary
Primary cilia are sensory organelles that project from the cell surface in most eukaryotic cells and affect signaling cascades in response to environmental stimuli. Degeneration of photoreceptors is a major cause of blindness, and Leber congenital amaurosis (LCA) is a recessively inherited form of retinal dystrophy resulting in severe visual loss in early childhood (Koenekoop, 2004). One of the most common causative LCA genes is CEP290 (centrosomal protein of 290 kDa; OMIM: 611755), accounting for around 15%– 25% of cases (Chacon-Camacho and Zenteno, 2015; den Hollander et al, 2006, 2008). CEP290 is found at the centrosome (Sayer et al, 2006), while in an interphase cell, CEP290 is located on both mother and daughter centrioles (Tsang et al, 2008). CEP290 forms a complex with CP110, another centrosomal protein, which leads to CEP290 inactivation until the cell enters quiescence, whereupon the CP110:CEP290 complex dissociates and CEP290 recruits Rab8a, a small GTPase, and triggers ciliogenesis (Tsang et al, 2008)
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