Different rate of retinal degenerations in mice with two distinct mutations in the Mitf gene

• Published in: Acta ophthalmologica (Oxford, England) Vol. 97; no. S263
• Main Authors: Eysteinsson, Thor, Jónasdóttir, Ingunn, García‐Llorca, Andrea, Björg Gudmundsdóttir, Thorunn, Ögmundsdóttir, Margrét Helga, Steingrímsson, Eiríkur
• Format: Journal Article
• Language: English
• Published: Malden Wiley Subscription Services, Inc 01-12-2019
• Subjects: Animals; Blindness; Cornea; Electroretinograms; Electroretinography; Epithelium; Heterozygotes; Ketamine; Microphthalmia-associated transcription factor; MITF gene; Mutation; Optical Coherence Tomography; Phenotypes; Photoreceptors; Pigmentation; Retina; Retinal degeneration; Retinal pigment epithelium; Structure-function relationships; Xylazine
• DOI: 10.1111/j.1755-3768.2019.5309
• EISSN: 1755-3768
• ISSN: 1755-375X

Purpose
The microphthalmia‐associated transcription factor (Mitf) gene is crucial for development of the retinal pigment epithelium (RPE) and photoreceptors. Loss of function mutations in this gene can cause ocular hypopigmentation, microphthalmia and blindness. Mice heterozygous for the Mitfmi‐wh/+ mutation have been used as a model for Waardenburg and Tietz syndromes in humans. The compound heterozygote Mitfmi‐wh/Mitfmi has two different mutant alleles in the Mitf gene each of which have quite severe effects on the phenotype. The purpose of this study was to examine changes over time in retinal function and structure in these mice, between 1 and 5 months of age, to elucidate the rate of progression of the retinal degenerations.
Methods
B6‐Mitfmi‐wh/+ and B6‐Mitfmi‐wh/Mitfmi mice were examined and compared to C5BL/6J mice as control. Mice were anesthetized by an intraperitoneal injection of 40 mg/kg‐1 Ketamine and 4 mg/kg‐1 Xylazine. Fundus and optical coherence tomography (OCT) images were obtained with a Micron IV. Flash electroretinography (ERG) from mice with a corneal electrode was used to determine retinal function.
Results
Fundus images from all mutant mice show hypopigmentation at 1 month, with large non‐pigmented areas forming at later stages. Mitfmi‐wh/+ mice are either blind or not at 1 month, with the ERG normal in amplitude in some animals and absent in others. The Mitfmi‐wh/+ mice with ERG responses at 1 month show slow retinal degeneration, with reduced responses at 5 months. Mitfmi‐wh/Mitfmi mice show either abnormal ERG responses at 1 month, or a flat ERG. The ERG responses in some of the Mitfmi‐wh/Mitfmi mice decrease with time, and at 4 months is flat. OCT images reveal that retinal layers in animals with flat ERG are thinner than in mice showing reduced ERG, but abnormally thin in both.
Conclusions
We conclude that Mitfmi‐wh/Mitfmi mutant mice show evidence of fast retinal degeneration. The Mitfmi‐wh/+ mutant mice are either blind at 1 month or show evidence of slow degeneration. Mice with these Mitf mutations may serve as models of retinal degenerations progressing at different rates, due to mutations in a gene expressed in the RPE.