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Francois Paquet-Durand, Ayse Sahaboglu, Dragana Trifunovic, Marius Ueffing, Thomas Euler; Retinitis Pigmentosa: Effects of homozygous vs. compound heterozygous Pde6b mutations on the progression of retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1715.
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Retinitis Pigmentosa (RP) is a group of hereditary retinal diseases, characterized by mutation-induced rod photoreceptor degeneration. Until today, no adequate treatment is available and the photoreceptor degeneration mechanisms remain poorly understood. Animal models used for the study of RP are usually homozygous for the causative genetic defect. Yet, in the human situation compound heterozygosity is the norm.
To study the effects of compound heterozygosity, we cross-bred the Pde6b mouse mutants rd1 and rd10. We used the TUNEL assay and a time-series to establish a time-line for the progression of photoreceptor cell death in homozygous rd1/rd1 and rd10/rd10, and in compound heterozygous rd1/rd10 retina. We then assessed the numbers of surviving photoreceptors at different post-natal (PN) time-points and correlated it with the length of the outer segments. Immunofluorescence was employed to assess the accumulation of cGMP, to indirectly estimate the activity of PDE6.
The analysis of cell death markers in the different mutants showed degeneration onsets ranging from PN11 (rd1), to PN14 (rd1/rd10), to PN18 (rd10). While the rd1 mouse degeneration was characterized by a single peak of cell death at PN13, in the rd1/rd10 there were two peaks of cell death at PN15 and PN24, a phenomenon that was even more marked in rd10 retina. Interestingly, the degeneration speed in rd1/rd10 was higher than in both rd1 and rd10 homozygous mutants.
Our results suggest that, while the degeneration onset is defined linearly by addition of genetic defects, the degeneration kinetics follow a non-linear pattern that may result from a complex interaction of PDE6 activity and outer segment length. Since many human RP patients suffer from compound heterozygous mutations, our study may have important implications for the translation of experimental animal work into clinical trials, in particular for determining the time-lines and optimal time-points for clinical interventions.
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