| First Author | Mookherjee S | Year | 2018 |
| Journal | Cell Rep | Volume | 25 |
| Issue | 3 | Pages | 611-623.e6 |
| PubMed ID | 30332642 | Mgi Jnum | J:270846 |
| Mgi Id | MGI:6278327 | Doi | 10.1016/j.celrep.2018.09.043 |
| Citation | Mookherjee S, et al. (2018) A CEP290 C-Terminal Domain Complements the Mutant CEP290 of Rd16 Mice In Trans and Rescues Retinal Degeneration. Cell Rep 25(3):611-623.e6 |
| abstractText | Mutations in CEP290 cause ciliogenesis defects, leading to diverse clinical phenotypes, including Leber congenital amaurosis (LCA). Gene therapy for CEP290-associated diseases is hindered by the 7.4 kb CEP290 coding sequence, which is difficult to deliver in vivo. The multi-domain structure of the CEP290 protein suggests that a specific CEP290 domain may complement disease phenotypes. Thus, we constructed AAV vectors with overlapping CEP290 regions and evaluated their impact on photoreceptor degeneration in Cep290(rd16/rd16) and Cep290(rd16/rd16);Nrl(-/-) mice, two models of CEP290-LCA. One CEP290 fragment (the C-terminal 989 residues, including the domain deleted in mutant mice) reconstituted CEP290 function and resulted in cone preservation and delayed rod death. The CEP290 C-terminal domain also improved cilia phenotypes in mouse embryonic fibroblasts and iPSC-derived retinal organoids carrying the Cep290(rd16) mutation. Our study strongly argues for in trans complementation of CEP290 mutations by a cognate fragment and suggests therapeutic avenues. |
