Structural and Functional Rescue of Murine Rod Photoreceptors by Human Rhodopsin Transgene

• Published in: Human molecular genetics 1999-07, Vol.8 (7), p.1309-1312
• Main Authors: McNally, Niamh, Kenna, Paul, Humphries, Marian M., Hobson, Audrey H., Khan, Noheed W., Bush, Ron A., Sieving, Paul A., Humphries, Peter, Farrar, G. Jane
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Genetic Therapy; Humans; Medical sciences; Mice; Mice, Transgenic; Ophthalmology; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinal Rod Photoreceptor Cells - physiology; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - therapy; Retinopathies; Rhodopsin - genetics; Transgenes
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/8.7.1309

Mice carrying a targeted disruption of the rhodopsin gene develop a severe degenerative retinopathy, failing to elaborate rod photoreceptor outer segments (ROS), having no recordable rod electroretinogram (ERG) and losing all of their rod cells over a period of ∼12 weeks. Murine and human rhodopsins differ in their amino acid sequences. Whether, or to what extent, such variability might influence the ability of human rhodopsin to serve as an adequate structural and functional substitute for the endogenous protein in mouse rod cells bears direct relevance to exploiting the full utility of Rho−/− animals as a model of degenerative retinal disease in man. We crossed Rho−/− mice with mice expressing a wild-type human rhodopsin transgene at levels approximating to those of the endogenous protein. Immunohistological examination of retinal selections from such animals demonstrated ROS of normal number and length and temporal expression of rhodopsin similar to that observed in wild-type animals; that is, immunoreactivity to an anti-rhodopsin antibody became clearly evident by day 3 post-partum. Whereas Rho−/− mice never display a rod ERG response, and even lose cone responses by 12 weeks of age, rescued mice showed 75% normal maximum amplitudes and had ERG b-wave thresholds (based on a 50 µ V criterion) within 0.1 log unit of normal wild-type at 20 weeks, and cone amplitudes remained normal at this age. These data demonstrate very substantial structural and functional rescue of the rod photoreceptors of Rho−/− mice and long-term preservation by the human rhodopsin transgene.