RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunction

Abstract

Dysfunction of primary cilia due to mutations in cilia-centrosomal proteins is associated with pleiotropic disorders. The primary (or sensory) cilium of photoreceptors mediates polarized trafficking of proteins for efficient phototransduction. Retinitis pigmentosa GTPase regulator (RPGR) is a cilia-centrosomal protein mutated in >70% of X-linked RP cases and 10%-20% of simplex RP males. Accumulating evidence indicates that RPGR may facilitate the orchestration of multiple ciliary protein complexes. Disruption of these complexes due to mutations in component proteins is an underlying cause of associated photoreceptor degeneration. Here, we highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and PGR-interacting proteins in severe genetic diseases, including retinitis pigmentosa, Leber congenital amaurosis (LCA), Joubert syndrome, and Senior-Loken syndrome, and explore the physiological relevance of photoreceptor ciliary protein complexes.

Figure 1

(A) Schematic of a rod photoreceptor cell showing the sensory cilium axoneme (Ax); TZ, transition zone; R, the rootlet; IS, inner segment; OS, outer segment connected by the TZ; N, nucleus. (B) Immunofluorescence image of photoreceptor layer of mouse retina stained with anti-acetylated a-tubulin antibody, a ciliary marker (green); ONL, outer nuclear layer.

Figure 2

Schematic representation of the predicted domain organization of human RPGR protein. P-Loop, ATP/GTP binding loop; RLD, RCC1-like domain; AP-sorting, adaptor protein sorting domain; Glu-Gly, glutamic acid and glycine rich domain; CC, coiled-coil domain.

Figure 3

Schematic representation of the RPGR and ciliarybasal bodycentrosomal (CBC) protein complexes in photoreceptors; binary interactions and macromolecular protein complexes facilitate microtubule-based ciliary transport. Dashed lines indicate interactions as part of complexes.