Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder

Authors

Monica Ardon
Lily Nguyen
Rui Chen
Jeffrey Rogers
Tim Stout
Sara Thomasy
Ala Moshiri

Publication Date

12-2-2024

Journal

Investigative Ophthalmology & Visual Science

DOI

10.1167/iovs.65.14.16

PMID

39641747

PMCID

PMC11629912

PubMedCentral® Posted Date

12-6-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Electroretinography, Tomography, Optical Coherence, Macaca mulatta, Cyclic Nucleotide Phosphodiesterases, Type 6, Retinal Cone Photoreceptor Cells, Disease Progression, Male, Female, Color Vision Defects, Disease Models, Animal, Mutation, Missense, Phenotype, Retinal Rod Photoreceptor Cells, Fluorescein Angiography, Homozygote, Cone Dystrophy, genetic diseases, ophthalmology, PDE6C, achromatopsia (ACHM), photoreceptors

Abstract

PURPOSE: The California National Primate Research Center contains a colony of rhesus macaques with a homozygous missense mutation in PDE6C (R565Q) which causes a cone disorder similar to PDE6C achromatopsia in humans. The purposes of this study are to characterize the phenotype in PDE6C macaques in detail to determine the onset of the cone phenotype, the degree to which the phenotype progresses, if heterozygote animals have an intermediate phenotype, and if rod photoreceptor function declines over time.

METHODS: We analyzed spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and electroretinography (ERG) data from 102 eyes of 51 macaques (aged 0.25 to 16 years). Measurements of retinal layers as well as cone and rod function over time were quantitatively compared.

RESULTS: Homozygotes as young as 3 months postnatal showed absent cone responses on electroretinogram. Infant homozygotes had reduced foveal outer nuclear layer (ONL) thickness compared with wildtype infants (P < 0.0001). Over 4 years of study, no consistent changes in retinal layer thicknesses were found within 5 adult homozygotes. However, comparisons between infants and adults revealed reductions in foveal ONL thickness suggesting that cone cells slowly degenerate as homozygotes age. The oldest homozygote (11 years) had reduced rod responses. Heterozygotes could not be distinguished from wildtypes in any parameters.

CONCLUSIONS: These data suggest that, like humans, macaque PDE6C heterozygotes are normal, and homozygote primates have absent cone function and reduced foveal ONL thickness from infancy. Cone photoreceptors probably degenerate over time and macular atrophy can occur. Rod photoreceptor function may wane in late stages.