Electroretinographic and OCT Retinal Morphologic Characterization of the Crx^Rdy Cat: An Animal Model for Severe Dominant Retinopathies Associated with CRX Mutations

Abstract

Purpose: The cone-rod homeobox (CRX) gene encodes a retina photoreceptor-specific transcription factor critical for photoreceptor (PR) development, function and survival. We have previously reported that cats heterozygous for a mutation in Crx have a severe, early PR dysfunction and degeneration and are an ideal model for dominant retinopathies caused by CRX mutations including Leber congenital amaurosis, cone-rod dystrophy, and retinitis pigmentosa. The purpose of this study was to fully characterize retinal function and retinal morphology of kittens heterozygous for the mutation and investigate the phenotype of kittens homozygous for the mutation.

Methods: Heterozygous (Crx^Rdy+/-), homozygous (Crx^Rdy-/-) kittens and control wild-type kittens had electroretinograms (ERG) and spectral-domain optical coherence tomography (SD-OCT) performed between 4 and 20 weeks of age.

Results: The dark-adapted ERG of the Crx^Rdy+/- kittens had markedly abnormal tracings while no ERG responses were recordable in the Crx^Rdy-/- kittens at any age. ERGs in wild-type kittens were well-developed at 4 weeks of age, whereas a- and b-waves were only recordable in the Crx^Rdy+/- kittens from ~6 weeks of age. B-wave threshold was elevated by ~2 log units; however a-wave threshold appeared similar to that of wild-type kittens. Both a- and b-waves had markedly reduced amplitudes and peaked at approximately 10 weeks of age in Crx^Rdy+/- kittens before declining until they were unrecordable at ~20 weeks of age. The ratio of b/a-waves was decreased in Crx^Rdy+/- kittens at all ages. Implicit times were increased. Light-adapted and cone flicker ERG responses could not be recorded from either Crx^Rdy-/- or Crx^Rdy+/- kittens at any age. OCT suggested abnormal PR architecture from 4 weeks of age in Crx^Rdy-/- kittens. In Crx^Rdy+/- kittens it showed retinal thinning spreading across the retina with age; which paralleled the ERG amplitude decreases.

Conclusions: Crx^Rdy kittens have a severe cone-rod dystrophy characterized by an abnormal morphology of PR layers, a lack of ERG response in Crx^Rdy-/- kittens and an incomplete maturation of ERG responses in Crx^Rdy+/- kittens. This study strengthens the previous description of the Crx^Rdy phenotype providing essential baseline information to investigate disease mechanism and therapy for dominant retinopathies caused by CRX mutations.

Keywords: 510 electroretinography: non-clinical • 696 retinal degenerations: hereditary • 648 photoreceptors