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Simon M Petersen-Jones, Laurence Occelli, Paige Winkler, Andrea Minella, Kelian Sun, Leslie Lyons, Anahita Daruwalla, Philip Kiser, Krzysztof Palczewski; New large animal model for RDH5-associated retinopathies. Invest. Ophthalmol. Vis. Sci. 2019;60(9):458.
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To characterize the genotype and further describe the phenotype of a large animal model with a degeneration of the area centralis (equivalent to the human macula) and visual streak (Petersen-Jones et al 2015. ARVO Abstracts, 65:3840).
The study involved a colony of cats in which a recessively inherited “macular degeneration” was segregating. Phenotyping was by electroretinography (ERG), funduscopy, confocal scanning laser ophthalmoscopy, spectral domain optical coherence tomography (SD-OCT), immunohistochemistry (IHC) and electron microscopy. Whole genome sequencing (WGS) of a trio of animals, including an affected offspring, was performed.
Variant calling of the WGS identified variants in potential retinal degeneration genes private to the trio of cats tested as compared to 113 normal cats. All affected cats were homozygous for a p(Gly181Val) missense variant in Rdh5. Modeling of this variant suggests it could affect Rdh5 dimer formation or cofactor binding. Rdh5 was not detectable by IHC of affected retina. There was a marked delay in recovery of dark-adapted ERG amplitudes following light exposure. Macular degeneration developed in ~70% of the cats homozygous for p(Gly181Val) by 18 months of age. Fundus imaging showed an initial hyporeflectivity in the area centralis and visual streak with an increase in autofluorescence in those areas, a thickening of the SD-OCT layers corresponding to outer segments, with loss of definition of the ellipsoid zone. Histologically this corresponded to a lengthening of photoreceptor outer segments with distortion of their distal tips. With progression there was a loss of photoreceptors within the area centralis until a single layer of photoreceptors remained.
A putative Rdh5 variant predicted to alter dimer formation or cofactor binding resulted in a lack of detectable Rdh5 in the retinal pigment epithelium of homozygous cats. The delay in dark-adapted ERG recovery was very similar to that reported in patients with RDH5-associated retinopathies. RDH5 mutations in human patients most commonly results in fundus albipunctatus but macular dystrophy is also reported. ~70% of cats homozygous for the Rdh5 p(Gly181Val) variant developed the “macular dystrophy” phenotype as juveniles or young adults. The variability in expression suggests either action of a modifying locus or possibly co-segregation of a mutation in a second retinal degeneration gene within this inbred colony.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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