The RP2 locus has been implicated as one cause of X-linked retinitis pigmentosa (XLRP), which is a devastating form of retinal degeneration. The RP2 gene encodes a ubiquitously expressed N-terminally acylated protein. Mutations eliminating RP2 acylation are linked to XLRP. The RP2 protein is normally found associated with the plasma membrane and its targeting to the plasma membrane in cultured cells requires N-terminal acylation. In photoreceptors, RP2 is localized to both inner and outer segments. RP2 shares sequence similarity with tubulin Cofactor c and has been shown to catalyze 2-tubulin folding in vitro. RP2 has also been shown to interact with an UNC119-ARL3 complex and exhibits GAP (GTPase activating protein) activity for ARL3. The physiological function of RP2 and the role RP2 gene mutations play in XLRP are yet to be defined. The goal of this proposal is to investigate the intracellular targeting mechanism of RP2 in photoreceptors and establish mouse models in order to better define the role RP2 plays in XLRP. This proposal consists of two aims;the experiments in the first aim set out to test the hypothesis that targeting of RP2 to outer segments in photoreceptors is dependent upon its N- terminal acylation.
The second aim focuses on generating a RP2 knock in mouse model expressing the RP2 protein which lacks N-terminal acylation. Characterization of the mice generated in Aim 2 will provide insight into the role RP2 plays in XLRP.
Retinitis Pigmentosa 2 (RP2) is a severe form of hereditary retinal disease that results in blindness. Advance in biomedical research has revealed that the cause is attributed to mutations in a special gene, but we still do not know why these mutations cause blindness, due in part to the lack of animals simulating this disease. The project outlined in this proposal describes generation of an animal model mimicking this disease, attempting to unlock the secret behind this disease and search for clues for future potential treatment.
| Zhang, Houbin; Hanke-Gogokhia, Christin; Jiang, Li et al. (2015) Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J 29:932-42 |
