Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond.

Chunbo Yang,Majlinda Lako,Sina Mozaffari-Jovin,Robin Ali,Lyle Armstrong,Robert Atkinson,Sushma Nagaraja-Grellscheid,Joseph Collin,Maria Georgiou,Jumana Al-Aama,Colin Johnson

doi:10.3389/fcell.2021.700276

Abstract

Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium that eventually results in blindness. Mutations in pre-mRNA processing factors (PRPF3, 4, 6, 8, 31, SNRNP200, and RP9) have been linked to 15–20% of autosomal dominant RP (adRP) cases. Current evidence indicates that PRPF mutations cause retinal specific global spliceosome dysregulation, leading to mis-splicing of numerous genes that are involved in a variety of retina-specific functions and/or general biological processes, including phototransduction, retinol metabolism, photoreceptor disk morphogenesis, retinal cell polarity, ciliogenesis, cytoskeleton and tight junction organization, waste disposal, inflammation, and apoptosis. Importantly, additional PRPF functions beyond RNA splicing have been documented recently, suggesting a more complex mechanism underlying PRPF-RPs driven disease pathogenesis. The current review focuses on the key RP-PRPF genes, depicting the current understanding of their roles in RNA splicing, impact of their mutations on retinal cell’s transcriptome and phenome, discussed in the context of model species including yeast, zebrafish, and mice. Importantly, information on PRPF functions beyond RNA splicing are discussed, aiming at a holistic investigation of PRPF-RP pathogenesis. Finally, work performed in human patient-specific lab models and developing gene and cell-based replacement therapies for the treatment of PRPF-RPs are thoroughly discussed to allow the reader to get a deeper understanding of the disease mechanisms, which we believe will facilitate the establishment of novel and better therapeutic strategies for PRPF-RP patients.

Highlights

Retinitis pigmentosa (RP) is the most common group of inherited retinal disorders characterized by progressive degeneration of photoreceptors and/or the retinal pigment epithelium (RPE)
Despite the morphological changes and functional deficiencies in mutant RPE, the photoreceptor cells in the mutant mice appear to be normal in histological and ultrastructural analyses and only at 24 months, the Prpf3T494M mice show decreased maximal rod a- and b-waves, but with no significant changes in cone b-wave. These findings suggest that RPE is the primary retinal cell type affected by Prpf mutations and the photoreceptor dysfunction is secondary to RPE impairment
In line with the decreased cilia length, cilia incidence and cilia malformation in PRPF31 mutant RPE cells and retinal organoids, the splicing and expression of important genes related to cilium assembly, cilium organization, microtubule organizing center and centrosome were affected by pre-mRNA processing factor (PRPF) mutations (Buskin et al, 2018)

Summary

Introduction

Retinitis pigmentosa (RP) is the most common group of inherited retinal disorders characterized by progressive degeneration of photoreceptors and/or the retinal pigment epithelium (RPE). Mutations in seven PRPF genes have been identified in adRP, including PRPF3, 4, 6, 8, 31, SNRNP200 (Brr2), and RP9 (PAP-1) (Mordes et al, 2006; Chen et al, 2014; Daiger et al, 2014; Ruzickova and Stanek, 2017), all of which except RP9 encode components of tri-snRNP and play important roles in the assembly of spliceosome complex B.

Results

Conclusion