Mutations in the microphthalmia-associated transcription factor (Mitf) gene can cause retinal pigment epithelium (RPE) and retinal dysfunction and degeneration. We examined retinal and RPE structure and function in 3 month old mice homo- or heterozygous or compound heterozygous for different Mitf mutations (Mitfmi-vga9/+, Mitfmi-enu22(398)/Mitfmi-enu22(398), MitfMi-Wh/+ and MitfMi-Wh/Mitfmi) which all have normal eye size with apparently normal eye pigmentation. Here we show that their vision and retinal structures are differentially affected. Hypopigmentation was evident in all the mutants while bright-field fundus images showed yellow spots with non-pigmented areas in the Mitfmi-vga9/+ mice. MitfMi-Wh/+ and MitfMi-Wh/Mitfmi mice showed large non-pigmented areas. Fluorescent angiography (FA) of all mutants except Mitfmi-vga9/+ mice showed hyperfluorescent areas, whereas FA from both Mitf-Mi-Wh/+ and MitfMi-Wh/Mitfmi mice showed reduced capillary network as well as hyperfluorescent areas. Electroretinogram (ERG) recordings show that MitfMi-Wh/+ and MitfMi-Wh/Mitfmi mice are severely impaired functionally whereas the scotopic and photopic ERG responses of Mitfmi-vga9/+ and Mitfmi-enu22(398)/Mitfmi-enu22(398) mice were not significantly different from wild type mice. Histological sections demonstrated that the outer retinal layers were absent from the MitfMi-Wh/+ and MitfMi-Wh/Mitfmi blind mutants. Our results show that Mitf mutations affect eye function, even in the heterozygous condition and that the alleles studied can be arranged in an allelic series in this respect.

PurposeThe Mitf (microphthalmia‐associated transcription factor) gene that is essential for the normal development of the retinal pigment epithelium (RPE). Mutations in this gene can cause hypopigmentation, microphthalmia and blindness. The purpose of this work was to analyze the retinal function and morphology in mice with specific Mitf mutations.MethodsThe following Mitf mutations were used: Mitfmi‐enu122 (398), Mitfmi‐wh/+, Mitfmi‐wh/Mitfmi and wild type (C5BL/6J) mice as a control. Mice were anesthetized by an intraperitoneal injection of 40 mg/kg−1 Ketamine and 4 mg/kg−1 Xylazine. Flash electroretinography (ERG), from mice with pupils dilated, with a corneal electrode and a reference electrode placed in the mouth, was used to determine the role of the MITF protein in retinal function. Histological retinal sections were stained with hematoxylin and eosin.ResultsERG recordings revealed that only one of the four mutants had any retinal function. The wild type mice had significantly higher mean amplitudes of the photopic a‐waves and scotopic oscillatory potentials than the Mitfmi‐enu122 (398) animals (α = 0.05). Furthermore, Mitfmi‐enu122 (398) had significantly shorter implicit times for the photopic b‐waves and c‐waves. Histology revealed that the RPE layer in the Mitfmi‐enu122 (398) and shows localized thinning of the RPE and their retinas look normal. However, the Mitfmi‐wh/+ showed a profound RPE degeneration and this layer is missing from the Mitfmi‐wh/Mitfmi animals. Furthermore, Mitfmi‐wh/+ and Mitfmi‐wh/Mitfmi have an immense retinal degeneration, lacking the photoreceptor and outer plexiform layers.ConclusionsThis study demonstrates that the Mitf gene has an impact on retinal function in mice, and the morphology of the neuroretina and the RPE.