Functional and Structural Characterization of a Large Animal Model of RDH5-Associated Retinopathy.

Abstract

Purpose: Inherited retinal diseases are a group of hereditary diseases that cause variable levels of blindness and affect a multitude of adults and children. One such disease is fundus albipunctatus (FA). FA is caused by autosomal recessive retinol dehydrogenase 5 (RDH5) mutations and results in rod dysfunction leading to night blindness and, in a subset of patients, macular degeneration (MD). We previously reported a spontaneous feline model of FA due to an RDH5 missense mutation. The affected cats showed rod dysfunction and a proportion developed degeneration of the area centralis (AC), equivalent to MD in humans.

Methods: We used fundus confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging, six different electroretinography protocols, immunohistochemistry, and histology/transmission electron microscopy to further characterize this large-animal cat model.

Results: In addition to rod dysfunction, cone recovery from intense stimulation was impaired. For RDH5-/- cats that developed AC degeneration, an initial elongation of rod outer segments with disorganization of the distal tips was initially detected in the AC and visual streak, suggestive of impaired shedding/phagocytosis. With progression, photoreceptors degenerated in the AC, matching the MD seen in some human patients.

Conclusions: The RDH5-/- cat model recapitulates features of both rod and cone dysfunction seen in human patients with RDH5 mutations.

Translational relevance: The RDH5-/- cat model offers a unique opportunity to further understand the mechanisms of RDH5-associated retinopathies and to investigate potential therapeutic approaches.