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

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


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.


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). Most RP cases start with night blindness due to the breakdown of rod photoreceptors, which are responsible for night vision. As the disease progresses, mid-peripheral vision is lost (tunnel vision), followed by cone degeneration leading to central vision loss until eventual blindness (Hartong et al., 2006; Berger et al., 2010). The prevalence of RP is around 1 in 4000 and there are over 1.5 million people suffering from this condition worldwide (Verbakel et al., 2018). There is no cure for RP although vitamins, nutritional supplementation and small molecules may slow disease progression.

To date, more than 70 genetic loci have been involved in the pathogenesis of RP1. Approximately half of RP cases have previous family history and fall into three Mendelian modes of inheritance: autosomal recessive (arRP), autosomal dominant (adRP), and X-linked recessive (xlRP) (Hamel, 2006). 50–60% of RP cases are caused by autosomal-recessive inheritance, 30–40% of cases are autosomal dominant, and 5–15% of cases are X-linked. Most of the genes involved in RP ontology are expressed specifically in the retina and/or RPE and contribute to photoreceptor or RPE function. Mutations in the rhodopsin (RHO) gene are the most common cause of adRP accounting for 25% of adRP cases. Interestingly, the second most common cause of adRP accounting for 15–20% of adRP cases, is linked to mutations in the ubiquitously expressed pre-mRNA processing factor (PRPF) genes, that encode core components of the spliceosome (Wang et al., 2019).

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