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

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.

Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue

“…A severe decrease in photoreceptor cell layer has been reported in the zebrafish by using Prfp31 morphants 51 , and the presence of apoptotic nuclei was previously observed in photoreceptors within late retinal organoids derived from PRPF31 patients iPSCs 29 . However, no defective photoreceptor phenotype was reported in different mouse models of splicing factors-linked RP 23 , 24 , 47 . It is not known why Prpf31 mutant mice have only an RPE degenerative phenotype and do not present the key phenotype of PRPF31 -related RP patients, i.e .…”

“…Several studies using human post-mortem retinas or patient lymphoblast cell lines showed the absence of specific PRPF31 isoforms in the retina, as well as both steady-state levels of snRNAs and processed pre-mRNAs highest in the retina, indicating the requirement of a particularly elevated splicing activity in this tissue 22 . Furthermore, the identification of which retinal cell type (RPE and/or photoreceptors) is primarily affected by mutations in the RNA splicing factors lead to a scientific debate 13 , 47 . To gain insights into PRPF31 -related RP, we characterized the cellular phenotype of RPE cells and retinal organoids derived from both clinically asymptomatic carriers and affected PRPF31 patients carrying two different mutations.…”

Genetic dissection of non-syndromic retinitis pigmentosa

“…[ 75 ] Variational hotspots for RP are associated with the U4 snRNP binding channel. [ 76 ] In a zebrafish model, it has been observed that variants affect this unwinding and result in rod cells demorphogenesis. But the pathogenic mechanism is yet unclear.…”

Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function

“…In contrast to these mutations, mutations in EXOSC2 are linked to a distinct syndrome, characterized by short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF), where the cerebellar atrophy is mild [92]. Given that mutations in pre-mRNA processing factors (PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, and RP9) have been linked to 15-20% of autosomal dominant retinitis pigmentosa, retinitis pigmentosa of EXOSC2-associated SHRF may be associated with misprocessing of pre-mRNAs and snR-NAs [93]. As other examples, mutations in PABPN1 have been linked to oculopharyngeal muscular dystrophy (OPMD) [94].…”