Abstract
Photoreceptor disease results in irreparable vision loss and blindness, which has a dramatic impact on quality of life. Pathogenic mutations in RP1L1 lead to photoreceptor degenerations such as occult macular dystrophy and retinitis pigmentosa. RP1L1 is a component of the photoreceptor axoneme, the backbone structure of the photoreceptor’s light-sensing outer segment. We generated an rp1l1 zebrafish mutant using CRISPR/Cas9 genome editing. Mutant animals had progressive photoreceptor functional defects as determined by electrophysiological assessment. Optical coherence tomography showed gaps in the photoreceptor layer, disrupted photoreceptor mosaics, and thinner retinas. Mutant retinas had disorganized photoreceptor outer segments and lipid-rich subretinal drusenoid deposits between the photoreceptors and retinal pigment epithelium. Our mutant is a novel model of RP1L1-associated photoreceptor disease and the first zebrafish model of photoreceptor degeneration with reported subretinal drusenoid deposits, a feature of age-related macular degeneration.
Highlights
Photoreceptors are sensory neurons that detect light via an elaborated cilium, called the outer segment (OS)
As the most frequent Occult macular dystrophy (OMD)-causing mutation occurs in the first doublecortin domain of human Retinitis Pigmentosa 1-Like 1 (RP1L1) and this region is well conserved between the species, we
Generation of rp1l1 Mutant Zebrafish targeted the homologous region in zebrafish rp1l1 using CRISPR/Cas9 genome editing
Summary
Photoreceptors are sensory neurons that detect light via an elaborated cilium, called the outer segment (OS). The photoreceptor OS contains membranous discs densely packed with opsins, the photosensitive proteins. As the outer segment is a modified cilium, pathogenic variants of ciliary components are common causes of photoreceptor disease [1,2]. The morphology of the outer segment distinguishes the two types of photoreceptors, cones and rods. Cones allow for high-acuity daytime and color vision, while rods are responsible for low-light vision. The human retina is organized such that the peripheral retina is rod dense and the central retina, termed the macula, is cone dense
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