Retinitis pigmentosa (RP) and allied retinal degenerations represent a major cause of visual loss in the United States.
Specific aim 1 of this competing renewal application is to relate mutations in genes expressed in rod photoreceptors to specific defects in activation and inactivation stages of rod phototransduction, rod light adaptation and rod dark adaptation. Through a subcontract with Dr. Stephen Daiger, we will determine the genes and mutations causing autosomal dominant disease in a subset of the large population of well-characterized patients at the Retina Foundation of the Southwest. Other collaborative arrangements have been established for identifying mutations in x-linked and recessive diseases. Using techniques developed during the last funding period, we will assess both activation and inactivation stages of phototransduction with the electroretinogram (ERG) in this rapidly growing cohort of patients with known mutations. Because of rapid advances in the understanding of processes underlying adaptation in vertebrate rods, we can relate adaptation defects in patients to the underlying physiology and biochemistry. We will use both ERG and psychophysical techniques to assess defects due to genes encoding proteins in the visual cycle. Parallel techniques will be used in recently available mouse models with targeted gene deletions of abcr, crx, and pptl, as well as transgenic mice with specific mutations in these genes. As in the abcr-/- and rpe65-/- models, these studies should help clarify the underlying defect and lead to pharmaceutical interventions.
Specific aim 2 is to extend the analysis of activation and inactivation stages of phototransduction to the cone system in anticipation that mutations affecting cone-specific proteins homologous to those found in rods will be found to cause some forms of cone, cone-rod and macular degeneration. Technical and conceptual breakthroughs from recent work on the derived rod photo response now make it possible to derive the smaller and much faster cone photo response from normal subjects and patients. There are several lines of evidence to suggest that visual pigment regeneration in cones occurs by a different mechanism than in rods. A quantitative analysis of the full time course of the cone photo response and measures of cone dark adaptation should help identify patients with cone-specific mutations. In the mouse models, cone measures will necessarily focus on the b-wave, using monochromatic stimuli, long-duration flashes, and flicker to optimize isolation of cone from rod responses.
Showing the most recent 10 out of 17 publications
