Abstract
The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice.
Highlights
The rd[1] mouse with a mutation in the phosphodiesterase 6b (Pde6b) gene was the first strain of mice identified with a retinal degeneration
As photoreceptor loss in these animals is slower, they provide a greater window of opportunity for treatment than the rd[1] mice. These results suggested that the retinal degeneration caused by a defective Pde6b gene is in principle amenable to structural and function rescue by gene therapy, but the rate of photoreceptor degeneration in the rd[1] mice is too fast to allow for effective rescue
Outside the area of b-subunit of rod PDE (bPDE) immunepositivity the outer nuclear layer (ONL) was severely reduced to a single layer, consistent with the known progress of retinal degeneration in rd[1] mice[4]
Summary
The rd[1] mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. Providing effective and lasting phenotypic rescue has proven elusive, the only achievement to date being partial histological preservation with minimal, if any, functional rescue[6,7,13,14] This has led to the development of a wide-spread notion that the speed of retinal degeneration in this model is too fast to allow a window of opportunity for treatment[14,15,16,17,18,19] This hypothesis has been bolstered by an effective gene supplementation therapy in the canine model of PDE6B deficiency (rcd[1] dog)[20] and in the hypomorphic Pde6b-mutant (rd10) mouse[15,18,19].
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