Grant: Project Grant

Retinitis pigmentosa (RP) is a devastating genetic disorder of the retina in which patients slowly lose their vision, resulting in blindness. The gene most commonly involved in RP is rhodopsin, which produces a protein that detects light. There are large quantities of rhodopsin protein in the light-sensitive rod photoreceptor cells of the retina. Mutations in the rhodopsin gene result in death of rods. However, it is unclear how rhodopsin mutations kill rods. It is proposed that because rods make so much rhodopsin, even subtle rhodopsin defects can result in drastic consequences. We pioneered the use of genetically modified Xenopus laevis frog tadpoles to study this problem. It is easy to make numerous types of genetic changes (e.g., different disease-causing mutations) in this animal to reproduce and compare different forms of the disease. We demonstrated that there are different types of rhodopsin mutations that kill rods in various ways. Two of these ways kill rods faster if the animals are exposed to light. Although the two light-exacerbated mechanisms are caused by mutations in the same gene, and although to an ophthalmologist, patients with these mutations appear to have the same disease, we find that these are actually two very distinct forms of RP that respond differently to treatment. In fact, certain treatments that benefit one form of RP actually worsen the other form. This has important implications for patient treatment: genetic testing will be necessary to test treatments and establish which treatments to use. We propose experiments that will help us understand how these mutations kill rod cells and key ways these mechanisms differ. Our new knowledge of the underlying cell death mechanisms, the unique genetic aspects of the system, and technical advances in manipulating the X. laevis genome will be of value to the scientific community and patients who suffer from RP.