Retinal Impairments in Mice Lacking Both Nxnl1 and Nxnl2 Genes.

Purpose: The protein products of the nucleoredoxin-like 1 (Nxnl1) gene have been proposed for their potential therapeutic benefit in retinitis pigmentosa (RP). Nxnl1 encodes two isoforms: rod-derived viability factor (RdCVF), which supports cone photoreceptor survival, and RdCVFL, which mitigates oxidative stress. Similarly, Nxnl2, a paralog of Nxnl1, encodes RdCVF2 and RdCVF2L, which also have photoreceptor protective properties. This study aimed to investigate whether the simultaneous disruption of Nxnl1 and Nxnl2 results in a more severe retinal phenotype on photoreceptor status compared to the disruption of either gene individually. Methods: Double Nxnl1-/-Nxnl2-/- mice were generated, and their retinal phenotype was compared to Nxnl1-/-, Nxnl2-/-, and Nxnl1+/+Nxnl2+/+ mice using spectral-domain optical coherence tomography (SD-OCT), fundus imaging, electroretinography (ERG), and immunofluorescence for retinal structure and cone density assessment. Results: In Nxnl1-/-Nxnl2-/- mice, SD-OCT revealed a significant reduction in outer nuclear layer (ONL) thickness at 3, 6, and 12 months of age. Rod dysfunction was observed at all ages with a significant decrease in both a- and b-wave amplitudes of the scotopic ERG. Although photopic single-flash and flicker ERGs remained normal, cone density was significantly reduced at 12.5 months of age. Additionally, retinal immunostaining confirmed impairments in both rod and cone photoreceptors. Conclusions: Nxnl1-/-Nxnl2-/- mice showed more severe structural and functional retinal deficits compared to the other groups at all ages, indicating that Nxnl1 and Nxnl2 exert non-redundant and/or complementary roles in maintaining photoreceptor function. These findings suggest that the combined products of Nxnl genes may yield more effective therapies for RP.