| First Author | Zhang H | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 3 | Pages | 932-42 |
| PubMed ID | 25422369 | Mgi Jnum | J:219642 |
| Mgi Id | MGI:5629447 | Doi | 10.1096/fj.14-257915 |
| Citation | Zhang H, et al. (2015) Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J 29(3):932-42 |
| abstractText | The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The Rp2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. Rp2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the Rp2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.-Zhang, H., Hanke-Gogokhia, C., Jiang, L., Li, X., Wang, P., Gerstner, C. D., Frederick, J. M., Yang, Z., Baehr, W. Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. |
