Abstract
Abstract: :
Purpose: The T4R mutation in canine rhodopsin (RHO) causes a dominantly inherited retinal degeneration. To better understand its pathogenesis, we have characterized the progressive retinal morphologic expression of this disease. Methods: Age matched RHO–/–, RHO+/– and wt dogs were enucleated at selected ages and their eyes were then either fixed in paraformaldehyde, embedded in OCT, and frozen–sectioned for immunocytochemistry; or fixed in a triple fixative, epon embedded and sectioned for morphological evaluation. Results: The location and severity of retinal degenerative lesions varied widely. In general, young dogs (8–9 weeks) showed no recognizable disease whereas older animals (> 10 months) exhibited severe retinal degeneration at least in distinct topographic regions. However, in the older animals, multiple stages of degeneration were noted in different locations, ranging from normal, particularly in the periphery, through complete photoreceptor and RPE loss. Early or mild disease was marked by focal increased shedding of discs from ROS, ROS shortening and increased pyknosis in the ONL. In more severe disease loci there was complete ONL loss. In general, disease was most severe centrally in the retina of older animals, but many isolated foci of degeneration were also observed scattered across the entire retina. Rhodopsin localized normally to the ROS, by immunocytochemical staining with antibodies directed against multiple epitopes of the protein. Other retinal antigens (e.g. cone opsin, RPE65 and insoluble IPM cone sheath) were expressed similarly between the mutant and wild type eyes in areas outside of degenerative foci. Within lesions, these cell markers reflected extreme remodeling of the degenerating retina. Conclusions: The RHO T4R mutant exhibits a severe retinal degeneration that mimics that seen in humans with similar defects, and provides an animal model to study mechanisms of disease and the efficacy of therapies for this class of retinal diseases.
Keywords: retinal degenerations: hereditary • microscopy: light/fluorescence/immunohistochemistry • pathology: experimental