RPGR is a ciliary protein mutated in a majority of X-linked RP cases (>75%) and is one of the most common cause of RP in humans. This project focuses on investigating the role of the TZ-associated protein RPGR in photoreceptor cilia. Our recent studies have revealed that RPGR exists in multiple protein complexes in mammalian retina, such as with Nephronophthisis (NPHP)-associated proteins and IFT proteins. Moreover, RPGR acts as a guanine exchange factor (GEF) for the small GTPase RAB8A, which is involved in cilia formation and photoreceptor protein trafficking. Our studies are specifically aimed at (i) delineating the role of RPGR as a GEF in photoreceptors, (ii) the cargo that is specifically delivered by RPGR to the outer segment, and (iii) the effect of human disease mutations on the function of RPGR. We have developed zebrafish and mouse models of RPGR dysfunction, which represent the human disease condition. Our investigations have also led to a successful gene therapy study to ameliorate RPGR-associated disease in two canine models.
The RP2 gene is mutated in 10-15% of X-linked RP cases. Previous studies indicate a role of RP2 in ciliary trafficking and maintenance. However, its precise role in photoreceptors is still unclear. Our lab utilizes cell culture and animal models to investigate the function of RP2 and pathology of associated disease.
CEP290 is another ciliary protein involved in regulating cilia formation. Mutations in CEP290 are a frequent cause of LCA, a childhood blindness disorder. Our lab has identified a naturally occurring mouse mutant of Cep290. Additionally, we have shown that CEP290 interacts with several distinct ciliary proteins in the retina and is involved in regulating protein trafficking as well as protein degradation. This project focuses on delineating the role of CEP290 in regulating photoreceptor cilia formation and maintenance and understanding the pathogenesis of CEP290-associated retinal degenerative diseases.