The long-term objective of this research is to elucidate the molecular and cell biology of photoreceptors. This project aims at discovering the mechanisms by which mutations of the rhodopsin gene lead to photoreceptor degeneration. Since photoreceptor dysfunction is a major cause of vision loss in patients with degenerative retinal disorders, knowledge gained from these studies has direct implications for understanding human eye diseases. Retinitis pigmentosa (RP) is a heterogeneous group of degenerative disorders that primarily affect photoreceptors and the retinal pigment epithelium. However, the clinical course of the different forms of RP follows a similar well-defined pattern. It is known that these disorders may be caused by mutations at various loci within the genome and therefore would involve separate genes. Accordingly, the different hereditary types of RP are not produced by an identical defect but the similar end results imply that they share some common steps in pathogenesis. So far, 75 point mutations of the rhodopsin gene have been identified in patients with autosomal dominant RP. However, the relationship between these mutations and the mechanisms of RP is not known. Although mutations of the rhodopsin gene cannot account for all the known hereditary types of RP, they offer a prototype for studying the pathogenesis of RP. The transgenic mouse approach can be a powerful method to study the effects of rhodopsin mutations. Transgenic mice that express normal or mutant forms of pig rhodopsin had been created in our laboratory. Of the 20 lines of transgenic mice derived from separate founder animals, 17 showed photoreceptor degeneration; each one of these 17 lines differs in the rate of degeneration. The 3 lines of transgenic mice that showed normal retinas (i.e. no degeneration) were expressing the normal form of pig rhodopsin at levels comparable to that of endogenous mouse rhodopsin. The 20 lines of transgenic mice offer us a unique animal model system to study by various methods the sequence of mechanisms involved in the pathogenesis of hereditary photoreceptor degeneration due to mutations in the rhodopsin gene. Once these mechanisms are identified and understood, some of the lethal effects due to mutations of the rhodopsin gene might be deterred through therapeutic intervention.
|Chang, G Q; Gaitan, A; Hao, Y et al. (1997) Correlation of DNA fragmentation and chromatin condensation in apoptotic nuclei of the Ser 6 mouse retina. Microsc Res Tech 36:123-9|