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The  RLBP1  gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in  RLBP1  are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod–cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the  rlbp1  gene in zebrafish and cell-specific expression of the paralogs  rlbp1a  in the retinal pigment epithelium and  rlbp1b  in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using  rlbp1a  and  rlbp1b  single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that  rlbp1a  was essential for cone photoreceptor function and chromophore metabolism in the fish eyes.  rlbp1a- mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11- cis  and all- trans -retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with  RLBP1  mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast,  rlbp1b  mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the  rlbp1a  single mutant. Together, our study showed that the  rlbp1a  zebrafish mutant recapitulated many features of human blinding diseases caused by  RLBP1  mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.

elife

Disturbed retinoid metabolism upon loss of  rlbp1a  impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina