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Laurence Mireille Occelli, Nicholas Minh Tran, Kristina Narfstrom, Shiming Chen, Simon M Petersen-Jones; Phenotypic characterization of cats homozygous for a frameshift mutation in Crx (CrxRdy/Rdy). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5395.
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© ARVO (1962-2015); The Authors (2016-present)
CRX is a transcription factor essential for normal photoreceptor development and survival. The Rdy cat has a spontaneous frameshift mutation in Crx. This type of mutation is similar to Class III CRX mutations that result in accumulation of mutant CRX protein which has a dominant negative action. The heterozygous cat (CrxRdy/+) has early dysfunction and degeneration of photoreceptors mimicking the severe Leber congenital amaurosis phenotype. This study investigated the phenotype of the homozygous cat (CrxRdy/Rdy).
CrxRdy/Rdy cats were investigated by ophthalmic examination, A-mode ultrasound (US), electroretinography (ERG), optical coherence tomography (OCT) and histology. Molecular changes were assessed by qRT-PCR, Western blot (WB) and immunohistochemistry (IHC).
CrxRdy/Rdy cats lacked vision and showed an absence of menace response and dazzle reflex. They also had a very decreased pupillary light reflex. Unlike the CrxRdy/+ cats, the CrxRdy/Rdy cats did not exhibit nystagmus. The globe length was significantly greater than that of wild-type kittens from as early as 1 month of age. Scotopic and photopic ERG responses were absent at all ages tested. CrxRdy/Rdy cats developed tapetal fundus hyperreflectivity detectable as early as 12 weeks of age but there was no obvious thinning of the retinal vasculature. The features of the photoreceptor inner/outer segments (IS/OS) were not discernible on OCT images from an early age. Failure of photoreceptor IS/OS development was confirmed by histology and IHC. Although the other retinal layers appeared relatively normal at 2 weeks of age, retinal stratification became increasingly abnormal with age. QRT-PCR in 2-week-old kittens revealed a decrease in cone and rod opsin mRNA levels while that of Crx was elevated. WB revealed that the amount of mutant Crx was greater than that of normal Crx protein in wild-type control retinas.
The retina of the CrxRdy/Rdy cat failed to fully mature resulting in blindness. Also, abnormal globe growth occurs such that the posterior segment of the globe becomes enlarged. Although relatively normal retinal stratification had developed at very early age, lack of normal development of photoreceptor IS/OS was noted and retinal layers became disorganized with disease progression. This was accompanied by a decrease in the expression of rod and cone opsins and absence of retinal function.
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