Progress in understanding retinitis pigmentosa (RP), a group of hereditary and presently incurable retinal degenerations, occurred recently with the discovery that, in the United States, nearly 25% of autosomal dominant (AD) forms of the disease result from mutations in the gene encoding the rod visual pigment, rhodopsin. An important question arising from these molecular genetic discoveries is: How does the molecular pathology lead to rod photoreceptor dysfunction and progressive retinal degeneration? A number of different scientific approaches, from the molecular to the clinical, are already proceeding toward answers to this question. We have initiated studies of ADRP patients in order to understand the relationship between the molecular lesions and the clinical phenotype. Patients representing 7 different point mutations in the rhodopsin gene were studied with non-invasive tests of retinal function that depend specifically on the properties of rhodopsin and rod photoreceptor physiology. These pilot studies showed that mildly affected ADRP patients with different rhodopsin genotypes have clearly different patterns of visual dysfunction. Furthermore, for each of the genotypes studied there was intrafamilial and interfamilial consistency of phenotypic expression. A finding of special interest was that certain genotypes had characteristic abnormalities in the time course of rod adaptation. These preliminary results should be extended to additional families and additional mutations. This application proposes to test the hypothesis that, if disease expression is determined with tests of rhodopsin and rod-mediated photoreceptor function, then there is a definable relationship between each ADRP rhodopsin genotype and the phenotype resulting therefrom.
Our specific aims are: to characterize the patterns of retinal dysfunction in a large series of patients representing 13 rhodopsin genotypes using psychophysics, electrophysiology and fundus reflectometry; to examine variations in pattern with progression of the diseases; to determine intrafamilial and interfamilial consistency of findings; and to quantify rod adaptation abnormalities found in certain genotypes with mathematical modeling. We will also test the specificity of phenotypic findings by studying ADRP patients with wild-type rhodopsin and extend our studies to more rhodopsin genotypes as well as other RP genotypes as they become available. The results of the proposed studies should permit the formulation and testing of hypotheses about the dysfunctional biochemical and physiological events within the rod photoreceptors of ADRP patients with rhodopsin mutations. Knowledge of the functional characteristics of each genotype should also be of value in planning future clinical studies of RP, especially in deciding which retinal mechanisms can and should be monitored in natural history studies and treatment trials of these patients.
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