Clinical and Molecular Aspects of C2orf71/PCARE in Retinal Diseases

Abstract

Mutations in the photoreceptor-specific C2orf71 gene (also known as photoreceptor cilium actin regulator protein PCARE) cause autosomal recessive retinitis pigmentosa type 54 and cone-rod dystrophy. No treatments are available for patients with C2orf71 retinal ciliopathies exhibiting a severe clinical phenotype. Our understanding of the disease process and the role of PCARE in the healthy retina significantly limits our capacity to transfer recent technical developments into viable therapy choices. This study summarizes the current understanding of C2orf71-related retinal diseases, including their clinical manifestations and an unclear genotype-phenotype correlation. It discusses molecular and functional studies on the photoreceptor-specific ciliary PCARE, focusing on the photoreceptor cell and its ciliary axoneme. It is proposed that PCARE is an actin-associated protein that interacts with WASF3 to regulate the actin-driven expansion of the ciliary membrane during the development of a new outer segment disk in photoreceptor cells. This review also introduces various cellular and animal models used to model these diseases and provides an overview of potential treatments.

Keywords: C2orf71 gene; PCARE; RPE; cilia; ciliopathies; cone-rod dystrophy; outer segment; photoreceptors; retina; retinitis pigmentosa.

Figure 1

Photoreceptor structure, connecting the cilium and retinal function of PCARE. (A) The cross-sectional view of the microtubule structure changes from a triplet microtubule structure (basal body, BB) to a doublet with Y-links (transition zone, TZ, or connecting cilium, CC), ending in a doublet configuration in the axoneme. The primary cilium of photoreceptor cells (rod and cone) is formed by the axoneme and ciliary membrane, growing from the BB and elongating through the outer segment of photoreceptor cells. The TZ, or CC, is located between the BB and axoneme. The yellow box indicates the CC region. (B) Schematic representation of CC, where its microtubule configuration with Y-links, as well as the intraflagellar transport (IFT) molecular motors kinesin (anterograde) and dynein (retrograde), are shown. (C) The proposed role of PCARE in specialized photoreceptor cilium. PCARE is located in the connecting cilium (CC) and recruits WASF3 protein from the cytoplasm to the CC. The PCARE-WASF3 complex activates ARP2/3 and promotes the formation of F-actin. This will cause remodeling and expansion of the ciliary membrane expansion and give rise to a new OS disk. The figure was created with BioRender.com.

Figure 2

RP54 and CRD-associated mutations in PCARE protein. Schematic representation of missense (red), frameshift (black), and nonsense (green) mutations. In the PCARE structure, colored columns represent the functional motifs: N-myristoylation (Gly2), S-palmitoylation (Cys3), coiled-coil domain (aa 318–333), two RP62 kinase-binding motifs, a WH2 acting binding motif (aa 597–615), three proline-rich regions (EVH1 domain-binding motifs) (aa 805–809, 830–834, 1056–1060), and a nuclear localization signal (aa 1042–1049).