Human mutant ELOVL4 causes retinal dystrophy in transgenic mice

Abstract

Abstract: : Purpose: The ELOVL4 protein shows homology to a family of proteins involved in the elongation of long–chain fatty acids. Mutations in the human ELOVL4 gene have been associated with autosomal dominant Stargardt–like macular dystrophy. Here we examine the functional consequence of mutant human ELOVL4 in transgenic mice. Methods: Human mutant ELOVL4 gene was expressed under an interphotoreceptor retinoid–binding protein (IRBP) promoter in mouse transgenic lines. Transgenic mice at ages 6–12 months (n=9), with three levels of expression (0.64, 4.1 and 5.27), were compared to mice with endogenous elovl4 (n=6). Standard full–field ERG responses were obtained from all mice. A high intensity a–wave protocol was conducted when amplitudes were of sufficient size. Nonparametric ANOVA median tests were used to evaluate the relationships among expression levels and ERG parameters. Color fundus photography was performed with a Kowa handheld RC–2 camera and 90 diopter Volk Lens. Results: An association was found between ERG amplitude and level of mutant ELOVL4 expression such that lower amplitudes were associated with increased expression (rod amplitude: p=0.007; cone amplitude, p=0.003). An analysis of a–wave parameters showed a significant effect on maximum photoresponse amplitude (Rmp3; p=0.009). No significant difference was found in gain (S); however amplitudes were too small for reliable estimates of S in high–expressing mice. Abnormalities in fundus appearance, including subretinal depigmented spots and geographic atrophy of retinal pigment epithelium (RPE), increased with expression level. Conclusions: Retinal dystrophy was evident in both retinal function indexed by the ERG and retinal imaging by fundus photography. The severity of retinal and RPE atrophy and ERG abnormalities in the transgenic mice were highly associated with expression levels of the mutant ELOVL4 protein. The ELOVL4 transgenic mouse provides a useful animal model for studying human macular degeneration.

Keywords: electroretinography: non–clinical • transgenics/knock–outs • retinal degenerations: hereditary