RGR-mediated photopic visual cycle and oxidative stress: potential mechanisms for cone vision impairment and retinal degeneration in retinitis pigmentosa linked to D1080N-IRBP

Interphotoreceptor retinoid-binding protein (IRBP), an extracellular glycoprotein, supports cone-mediated vision through unclear molecular mechanisms. Over 30 different mutations in the <i>IRBP</i> gene have been found in patients with retinitis pigmentosa, childhood-onset retinal dystrophy with high myopia, and cone-rod dystrophy, yet their pathogenicity and underlying pathogenic mechanisms have not been studied in animal models. Here, we found that extracellular IRBP significantly increased the quantities of the extracellular, but not intracellular, 11-<i>cis</i>-retinol and 11-<i>cis</i>-retinal synthesized by retinal G protein-coupled receptor (RGR) in coordination with retinol dehydrogenases and green light stimuli. Retinoid trafficking in the retina and recovery of S-cone and rod maximum photoresponses were substantially delayed in male and female mice of a new retinitis pigmentosa model linked to the human D1080N-IRBP. The mutant IRBP was unstable, not secreted, and retained in the endoplasmic reticulum of photoreceptors due to formation of insoluble high molecular complexes via disulfide bonds. Young mutant mice exhibited profound reduction in photoresponses to ultraviolet stimuli without a significant S-opsin reduction and S-cone structural degeneration. In contrast, M-cones exhibited early and progressive degeneration, accompanied by mislocalization of M-opsin to the soma and synaptic region of M-cones. Rods also underwent early and progressive degeneration. Oxidative and inflammatory stresses as well as pro-apoptotic proteins such as activated caspase-3, BAX, and apoptosis-inducing factor were markedly increased in the mutant mouse retina. These findings identify both a role of IRBP in the RGR-mediated photopic visual cycle supporting daytime color vision and the molecular mechanism by which D1080N-IRBP causes vision impairment and photoreceptor degeneration.<b>Significance Statement</b> IRBP, an interphotoreceptor matrix protein, supports cone-mediated color vision via unclear mechanism. Mutations in IRBP are associated with blinding diseases with poorly understood pathogenic mechanism. Here, we found that IRBP plays an important role in the RGR-mediated photopic visual cycle essential cone-mediated vision. Consistent with this, recovery of S-cone photoresponse was significantly delayed in a newly developed mouse model carrying a human disease-causing IRBP mutation. This mutation abolished IRBP secretion and led to progressive degeneration of rods and M-cones, accompanied by elevation of oxidative stress, inflammatory cytokines, and proapoptotic proteins in the retina. These results identify both a functional mechanism of IRBP in promoting cone-mediated vision and a pathogenic mechanism by which IRBP mutations cause vision loss and photoreceptor degeneration.