A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype

Abstract Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 2022-04, Vol.31 (8), p.1263-1277
Main Authors: Occelli, Laurence M, Daruwalla, Anahita, De Silva, Samantha R, Winkler, Paige A, Sun, Kelian, Pasmanter, Nathaniel, Minella, Andrea, Querubin, Janice, Lyons, Leslie A, Robson, Anthony G, Heon, Elise, Michaelides, Michel, Webster, Andrew R, Palczewski, Krzysztof, Vincent, Ajoy, Mahroo, Omar A, Kiser, Philip D, Petersen-Jones, Simon M
Format: Article
Language:English
Subjects:
Alcohol Oxidoreductases - genetics
Animals
Atrophy
Cats
Electroretinography
Humans
Macular Degeneration
Mice
Models, Animal
Original
Phenotype
Retinal Diseases - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5−/− mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddab316