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The gene coding for centrosomal protein 290 (CEP290), a large multidomain protein, is the most frequently mutated gene underlying the non-syndromic blinding disorder Leber's congenital amaurosis (LCA).  CEP290  has also been implicated in several cilia-related syndromic disorders including Meckel–Gruber syndrome, Joubert syndrome, Senor–Loken syndrome and Bardet–Biedl syndrome (BBS). In this study, we characterize the developmental and functional roles of  cep290  in zebrafish. An antisense oligonucleotide [Morpholino (MO)], designed to generate an altered  cep290  splice product that models the most common LCA mutation, was used for gene knockdown. We show that  cep290  MO-injected embryos have reduced Kupffer's vesicle size and delays in melanosome transport, two phenotypes that are observed upon knockdown of  bbs  genes in zebrafish. Consistent with a role in cilia function, the  cep290  MO-injected embryos exhibited a curved body axis. Patients with LCA caused by mutations in  CEP290  have reduced visual perception, although they present with a fully laminated retina. Similarly, the histological examination of retinas from  cep290  MO-injected zebrafish revealed no gross lamination defects, yet the embryos had a statistically significant reduction in visual function. Finally, we demonstrate that the vision impairment caused by the disruption of  cep290  can be rescued by expressing only the N-terminal region of the human CEP290 protein. These data reveal that a specific region of the CEP290 protein is sufficient to restore visual function and this region may be a viable gene therapy target for LCA patients with mutations in  CEP290 .

The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness