The R345W-fibulin-3 mutation increases the sensitivity of the outer retina to damage caused by sodium iodate

Abstract

Purpose : Malattia Leventinese (ML), an autosomal dominant inherited degenerative eye disease, is caused by a point mutation (R345W) in the fibulin-3 (Fib3) gene (efemp1) that results in hyperreflective foci (detected by optical coherence tomography) in association with sub-retinal pigment epithelium (RPE) drusen and hyper-pigmentation. The purpose this study was to determine the extent of augmentation of hyperreflectivity caused by sodium iodate (SI)-induced retinal degeneration in mice carrying the R345W fib3 mutation.

Methods : Eighteen C57 three-month-old male and female mice were injected with SI dissolved in PBS at 15, 30, 45, or 60 mg/kg. Spectral-domain optic coherence topography (SD-OCT) images were acquired 7 days later (Bioptigen). Frozen vertical retinal cross-sections (10 µm thick) of eyes from wild-type (WT), heterozygous (Fib3^+/ki), and homozygous (Fib3^ki/ki) mice were processed for H&E staining.

Results : Hyperreflective foci (HRF) were detected by SD-OCT in the retinas of WT mice given 45 and 60 mg/kg, but not in those given 15 and 30 mg/kg. H&E sections appeared normal in the control mice, and in the WT mice that received 15 and 30 mg/kg of SI. The retinas of WT mice receiving 45 and 60 mg/kg were thinner than the control (31.2% and 27.1%, p<0.001), due to the loss of tissue in the photoreceptor layer. Thinning of the ONL and disorganization of the RPE layer was also noted. Hyperreflective foci were evident in Fib3^+/ki and Fib3^ki/ki mice given SI at 30, 45, and 60 mg/kg but were not apparent in mice given 15mg/kg. H&E images followed a similar trend, with the 15mg/kg dose looking similar to the controls, whereas sections from Fib3^+/kiand Fib3^ki/ki mice treated with 30, 45, and 60mg/kg presented with pigmented lesions in the neural retina.

Conclusions : The results suggest that SI causes HRF and induces pigment migration into the neural retina in WT mice. Furthermore, presence of the fib3 mutation increases sensitivity to SI exposure, leading to more dramatic retinal degeneration and pigment migration. Our results suggest that the R345W mutation increases susceptibility of the outer retina and RPE to chemical or metabolic insult.

This is a 2021 ARVO Annual Meeting abstract.