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Richard J. Davis, Joaquin Tosi, Kerstin M. Janisch, J. Mie Kasanuki, Nan-Kai Wang, Jian Kong, Ilene Tsui, Marianne Cilluffo, Michael L. Woodruff, Gordon L. Fain, Chyuan-Sheng Lin, Stephen H. Tsang; Functional Rescue of Degenerating Photoreceptors in Mice Homozygous for a Hypomorphic cGMP Phosphodiesterase 6 b Allele (Pde6b H620Q ). Invest. Ophthalmol. Vis. Sci. 2008;49(11):5067-5076. doi: https://doi.org/10.1167/iovs.07-1422.
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purpose. Approximately 8% of autosomal recessive retinitis pigmentosa (RP) cases worldwide are due to defects in rod-specific phosphodiesterase PDE6, a tetramer consisting of catalytic (PDE6α and PDE6β) and two regulatory (PDE6γ) subunits. In mice homozygous for a nonsense Pde6b rd1 allele, absence of PDE6 activity is associated with retinal disease similar to humans. Although studied for 80 years, the rapid degeneration Pde6b rd1 phenotype has limited analyses and therapeutic modeling. Moreover, this model does not represent human RP involving PDE6B missense mutations. In the current study the mouse missense allele, Pde6b H620Q was characterized further.
methods. Photoreceptor degeneration in Pde6b H620Q homozygotes was documented by histochemistry, whereas PDE6β expression and activity were monitored by immunoblotting and cGMP assays. To measure changes in rod physiology, electroretinograms and intracellular Ca2+ recording were performed. To test the effectiveness of gene therapy, Opsin::Pde6b lentivirus was subretinally injected into Pde6b H620Q homozygotes.
results. Within 3 weeks of birth, the Pde6b H620Q homozygotes displayed relatively normal photoreceptors, but by 7 weeks degeneration was largely complete. Before degeneration, PDE6β expression and PDE6 activity were reduced. Although light-/dark-adapted total cGMP levels appeared normal, Pde6b H620Q homozygotes exhibited depressed rod function and elevated outer segment Ca2+. Transduction with Opsin::Pde6b lentivirus resulted in histologic and functional rescue of photoreceptors.
conclusions. Pde6b H620Q homozygous mice exhibit a hypomorphic phenotype with partial PDE6 activity that may result in an increased Ca2+ to promote photoreceptor death. As degeneration in Pde6b H620Q mutants is slower than in Pde6b rd1 mice and can be suppressed by Pde6b transduction, this Pde6b H620Q model may provide an alternate means to explore new treatments of RP.
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