A conditional Mitf mouse model of geographic atrophy (GA)

Abstract

Purpose Mice carrying different mutations in the microphthalmia‐associated transcription factor (Mitf) gene, affect the normal the retinal pigment epithelium (RPE) resulting in microphthalmia. The MitfK243R/K243R; Tyr::Cre mice have an induced conditional mutation, where Lysine 243 is mutated to Arginine, thus affecting DNA binding. The purpose of this study was to characterize eye development and function in these mutant mice. Our analysis shows retinal degeneration and slow progressive GA in the eyes of these mice. Methods C5BL/6J (wild type) and MitfK243R/K243R; Tyr::Cre mice of 1, 3 and 12 months old were used in this study. Fundus and optical coherence tomography (OCT) images were taken from wild type and mutant mice. Retinal function was assessed by electroretinography (ERG). RNA isolation from posterior eye cups and reverse‐transcription quantitative PCR (RT‐qPCR) were done to analyze Mitf mRNA expression. Results Bright field images indicate that eyes from B6‐MitfK243R; Tyr::Cre mice have alternating areas of severe hypo‐ and hyperpigmentation and vascular abnormalities. OCT images from 1 and 3 months old mutants demonstrated that some regions of the retina have the RPE, photoreceptor and neuronal layers intact, while neighboring areas show severe degeneration of these cell types. However, at one year of age the RPE, photoreceptor and outer retina layers are missing in the mutants. ERG recordings revealed that at 1 and 3 months old the mutants had significantly reduced (p < 0.05) photopic b‐wave, scotopic a‐ and b‐waves, while at 12 months old the mutant cone and rod ERG responses were flat or severely reduced compared to wild type. Gene expression analysis showed that Mitf expression was elevated in the mutants as compared to wild type, suggesting compensatory mechanisms. Conclusions We have found that mice with the MitfK243R conditional mutation driven by the Tyr::Cre driver may be the first mouse model of slow progressive retinal GA. This mutant shows similar characteristic as seen in human age‐related macular degeneration (AMD) and may therefore provide a model for that disease.