ABSTRACT
Mutations in the PROMININ-1 (PROM1) gene are associated with inherited, non-syndromic vision loss. Here, we used CRISPR/Cas9 to induce truncating prom1-null mutations in Xenopus laevis to create a disease model. We then tracked progression of retinal degeneration in these animals from the ages of 6 weeks to 3 years old. We found that retinal degeneration caused by prom1-null is age-dependent and likely involves death or damage to the retinal pigment epithelium (RPE) that precedes photoreceptor degeneration. As prom1-null frogs age, they develop large cellular debris deposits in the subretinal space and outer segment layer which resemble subretinal drusenoid deposits (SDD) in their location, histology, and representation in color fundus photography and optical coherence tomography (OCT). In older frogs, these SDD-like deposits accumulate in size and number, and they are present before retinal degeneration occurs. Evidence for an RPE origin of these deposits includes infiltration of pigment granules into the deposits, thinning of RPE as measured by OCT, and RPE disorganization as measured by histology and OCT. The appearance and accumulation of SDD-like deposits and RPE thinning and disorganization in our animal model suggests an underlying disease mechanism for prom1-null mediated blindness of death and dysfunction of the RPE preceding photoreceptor degeneration, instead of direct effects upon photoreceptor outer segment morphogenesis, as was previously hypothesized.
