Cat LCA-CRX Model, Homozygous for an Antimorphic Mutation Has a Unique Phenotype

Purpose: Mutations in the CRX transcription factor are associated with dominant retinopathies often with more severe macular changes. The CRX-mutant cat (RdyA182d2) is the only animal model with the equivalent of the critical retinal region for high-acuity vision, the macula. Heterozygous cats (CRXRdy/+) have a severe phenotype modeling Leber congenital amaurosis. This study reports the distinct ocular phenotype of homozygous cats (CRXRdy/Rdy). Methods: Gene expression changes were assessed at both mRNA and protein levels. Changes in globe morphology and retinal structure were analyzed.Results: CRXRdy/Rdy cats had high levels of mutant CRX mRNA and protein. The expression of photoreceptor target genes was severely impaired although there were variable effects on the expression of other transcription factors. The photoreceptor cells remained immature and failed to elaborate outer segments consistent with the lack of retinal function. The retinal layers displayed a progressive remodeling with cell loss but maintained overall retinal thickness due to gliosis. Rapid photoreceptor loss largely occurred in the macula-equivalent retinal region. The homozygous cats developed markedly increased ocular globe length.Conclusions: The phenotype of CRXRdy/Rdy cats was more severe compared to CRXRdy/+ cats by several metrics. Translational Relevance: The CRX-mutant cat is the only model for CRX-retinopathies with a macula-equivalent region. A prominent feature of the CRXRdy/Rdy cat phenotype not detectable in homozygous mouse models was the rapid degeneration of the macula-equivalent retinal region highlighting the value of this large animal model and its future importance in the testing of translational therapies aiming to restore vision.