The microphthalmia-associated transcription factor (Mitf) gene and its role in regulating eye function

Andrea García-Llorca,Thor Eysteinsson,Margret Helga Ogmundsdottir,Eiríkur Steingrimsson,Snaefridur Gudmundsdottir Aspelund

doi:10.1038/s41598-019-51819-0

Andrea García-Llorca, Thor Eysteinsson + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-51819-0

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Abstract

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.

Highlights

Mutations in the microphthalmia-associated transcription factor (Mitf) gene can cause retinal pigment epithelium (RPE) and retinal dysfunction and degeneration
Our analysis shows that Mitf is important for normal adult eye size and external structure but is critical for normal retinal function at 3 months of age
We found that despite some depigmentation of the RPE, two of the mutants, Mitfmi-vga9/+ and Mitfmi-enu22(398)/Mitfmi-enu22(398) have normal adult eye size and external structure and have functioning retinas

Summary

Introduction

Mutations in the microphthalmia-associated transcription factor (Mitf) gene can cause retinal pigment epithelium (RPE) and retinal dysfunction and degeneration. One of the major causes of visual impairment and blindness in humans are retinal degenerations These are either due to inheritance of mutations in genes known to cause defects in the retina or the retinal pigment epithelium (RPE)[1,2,3,4,5]. The most studied of these transcription factors, are the homeodomain transcription factors Crx[15] and Otx[216–20], the retina-specific basic motif-leucine zipper (bZIP) transcription factor NRL21,22, and the microphthalmia-associated transcription factor family Mitf-Tfe[15,18,23] Mutations in these transcription factors can lead to retinal degeneration. Coat color lighter than dilute (d/d); eyes dark ruby; spots on feet, tail and belly; inner ear defects

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