PRPH2/RDS and ROM-1: Historical context, current views and future considerations

Abstract

Peripherin 2 (PRPH2), also known as RDS (retinal degeneration slow) is a photoreceptor specific glycoprotein which is essential for normal photoreceptor health and vision. PRPH2/RDS is necessary for the proper formation of both rod and cone photoreceptor outer segments, the organelle specialized for visual transduction. When PRPH2/RDS is defective or absent, outer segments become disorganized or fail to form entirely and the photoreceptors subsequently degenerate. Multiple PRPH2/RDS disease-causing mutations have been found in humans, and they are associated with various blinding diseases of the retina such as macular degeneration and retinitis pigmentosa, the vast majority of which are inherited dominantly, though recessive LCA and digenic RP have also been associated with RDS mutations. Since its initial discovery, the scientific community has dedicated a considerable amount of effort to understanding the molecular function and disease mechanisms of PRPH2/RDS. This work has led to an understanding of how the PRPH2/RDS molecule assembles into complexes and functions as a necessary part of the machinery that forms new outer segment discs, as well as leading to fundamental discoveries about the mechanisms that underlie OS biogenesis. Here we discuss PRPH2/RDS-associated research and how experimental results have driven the understanding of the PRPH2/RDS protein and its role in human disease.

Keywords: Photoreceptors PRPH2; RDS; ROM-1; Retinal degeneration; Tetraspanin.

Figure 1. PRPH2/RDS deficiency leads to abnormalities in retinal structure

Retinal structure was evaluated at postnatal day 30 in murine retinas of the indicated genotypes. Top row shows light micrographs collected at 40×, bottom row shows transmission electron micrographs collected at 3,000×. Scale bars: 10μm. RPE: retinal pigment epithelium, OS: outer segment, IS: inner segment, ONL: outer nuclear layer, INL: inner nuclear layer.

Figure 2. Mutations and functional domains within the PRPH2/RDS molecule

The PRPH2/RDS molecule is illustrated with selected mutations labeled on the left and functional domains labeled on the right. Mutations and functional diagrams on the illustration are those to which we refer directly here, additional pathogenic mutations in PRPH2/RDS exist and can be explored by visiting http://www.retina-international.org/files/sci-news/rdsmut.htm.

Figure 3. PRPH2/RDS localization in the rim. A-B

Shown are illustrations of the base of a rod (A) and cone (B) photoreceptor adjacent to the connecting cilium. Blue lines illustrate the axoneme, purple molecules indicate PRPH2/RDS. In rods, PRPH2/RDS is found on the “closed” edge of nascent discs and all the way around the circumference of fully formed discs. In cones, PRPH2/RDS is likewise found along “closed” rims only. C. Illustration showing that the curvature of the open rims is opposite that of the closed rims and would therefore not accommodate PRPH2/RDS in the orientation it is known to adopt in which the D2 loop (shown in black in C) mediates interactions between adjacent PRPH2/RDS molecules.

Figure 4. PRPH2/RDS and ROM-1 assemble into complexes

The core unit of RDS/ROM-1 complexes is the homo/heterotetramer. These tetramers assemble into disulfide linked RDS/ROM-1 hetero-oligomers of intermediate size and large higher-order homo-oligmers. These complexes are found in the disc rim with the disulfide-linked D2 loop protruding into the intradiscal space. Rim packing estimates are from (Kevany et al., 2013).

Figure 5. Mutations in PRPH2/RDS lead to phenotypic changes in the retina

Shown are brightfield fundus images (A) and fluorescein angiograms (B) from animals aged 5-6 months of the indicated genotypes. Though the rds^+/− (a model of ADRP) exhibits no dramatic changes in the fundus/angiogram at this age, different MD mutations lead to striking phenotypes, including abnormalities in retinal vasculature in the case of R172W transgenic animals, and fundus speckling (arrows) in Y141C heterozygous knockin animals.