A Murine Rp1 Missense Mutation Causes Protein Mislocalization and Slowly Progressive Photoreceptor Degeneration

Abstract

Mutations in the RP1 gene can cause retinitis pigmentosa. We identified a spontaneous L66P mutation caused by two adjacent point mutations in the Rp1 gene in a colony of C57BL/6J mice. Mice homozygous for the L66P mutation exhibited slow, progressive photoreceptor degeneration throughout their lifespan. Optical coherence tomography imaging found abnormal photoreceptor reflectivity at 1 month of age. Histology found shortening and disorganization of the photoreceptor inner and outer segments and progressive thinning of the outer nuclear layer. Electroretinogram a- and b-wave amplitudes were decreased with age. Western blot analysis found that the quantity and size of the mutated retinitis pigmentosa 1 (RP1) protein were normal. However, immunohistochemistry found that the mutant Rp1 protein partially mislocalized to the transition zone of the shortened axonemes. This mutation disrupted colocalization with cytoplasmic microtubules in vitro. In conclusion, the L66P mutation in the first doublecortin domain of the Rp1 gene impairs Rp1 protein localization and function, leading to abnormalities in photoreceptor outer segment structure and progressive photoreceptor degeneration. This is the first missense mutation in Rp1 shown to cause retinal degeneration. It provides a unique, slowly progressive photoreceptor degeneration model that mirrors the slow degeneration kinetics in most patients with retinitis pigmentosa.

Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration

“…11 We have found progressive outer retina (photoreceptor layer) thinning by SD-OCT in mice caused by a mutation in Rp1, a microtubule-associated protein. 12 Thus we hypothesized that SD-OCT may show photoreceptor abnormalities in patients with FTD tauopathy since tau is also a microtubule-associated protein. In this study, we evaluated retinal layer thicknesses using SD-OCT in a large wellcharacterized cohort of patients with FTD compared to controls.…”

Molecular basis for photoreceptor outer segment architecture

“…Like many microtubule-associated proteins (MAPs), RP1 promotes microtubule polymerization and stability, and elegant in vivo analyses show that loss of the DCX domain reduces photoreceptor axoneme length in murine retina (Liu et al, 2004). A more recent study using a spontaneously occurring L66P mutation, confirms these findings (Song et al, 2014). Although interactions with proteins other than tubulin have not been identified to date, the expression of retinal disease in murine RP1 models is strongly affected by the genetic background.…”

Berberine protects against light-induced photoreceptor degeneration in the mouse retina

“…As described previously (Song et al, 2014a), artificial tears were used throughout the procedure to protect the corneas and maintain corneal clarity, and mice were seated in the Bioptigen AIM-RAS holder. Spectral domain OCT images were obtained with the Envisu R2200-HR SD-OCT device (Bioptigen, Durham, NC).…”