A novel candidate gene, DUSP4 implicated in high myopia

Abstract

Purpose : Myopia, the most common eye disorder, is caused by genetic and environmental factors. Complete congenital stationary night blindness (cCSNB) is caused by mutations in genes expressed in ON-bipolar cells and is associated with high myopia. Whole transcriptome sequencing on mouse models of cCNSB revealed differentially expressed genes potentially explaining high myopia in cCSNB (Zeitz et al. Prog Ret Eye Res. 2023). One of those was DUSP4, which encode the dual-specificity phosphatase 4, that dephosphorylates mitogen-activated protein kinases (MAPKs). The aim of this study was to examine the role of DUSP4 in the retina and its possible implication in myopia.

Methods : Phenotyping of 6-month-old Dusp4^+/+ and Dusp4^-/- was performed using spectral-domain optical-coherence tomography, electroretinogram (ERG) and optomotor measurements. Expression and localization studies were done by RT-qPCR, western blot and immunofluorescence microscopy. Retinal levels of dopamine and its metabolite 3,4 dihydroxyphenylacetic acid were measured using ultra performance liquid chromatography. Myopia was induced by placing a -25 D lens in front of the right eye of 3-week-old mice for 3 weeks (lens-induced myopia, LIM). Refractive development and LIM were measured as previously (Wilmet et al, IJMS, 2022).

Results : Dusp4 was shown to be expressed in the inner nuclear layer and localized to ON- and OFF-bipolar cells. While the retinal structure was unaltered in Dusp4^-/- mice, visual acuity was reduced under scotopic and photopic conditions at lower spatial frequencies, and the amplitudes of ERG a-waves and b-waves were increased under scotopic conditions (p<0.05). Phospho-MAPK levels were increased in the retinas of Dusp4^-/- mice. The expression and immunolocalization of DUSP4 was severely reduced in mouse models of cCNSB, most likely due to the absence of DUSP4 in ON-bipolar cells. Dopamine metabolism was altered in Dusp4^-/- mice compared to Dusp4^+/+. Refractive eye development in Dusp4^-/- mice was similar to Dusp4^+/+ mice; however, after 3 weeks of LIM, preliminary data showed a larger myopic shift in Dusp4^-/- eyes compared to wild type.

Conclusions : Our results indicate that Dusp4 expression in ON-bipolar cells and the MAPK pathway is important for retinal function and emmetropization. This highlights the contribution of the retinal ON-pathway in regulating axial growth of the eye.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.