Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy

Wheway, Gabrielle; Douglas, Andrew; Baralle, Diana; Guillot, Elsa

Abstract

Pathogenic variants in pre-messenger RNA (pre-mRNA) splicing factor 31, PRPF31, are the second most common genetic cause of autosomal dominant retinitis pigmentosa (adRP) in most populations. This remains a completely untreatable and incurable form of blindness, and it can be difficult to predict the clinical course of disease. In order to design appropriate targeted therapies, a thorough understanding of the genetics and molecular mechanism of this disease is required. Here, we present the structure of the PRPF31 gene and PRPF31 protein, current understanding of PRPF31 protein function and the full spectrum of all reported clinically relevant variants in PRPF31. We delineate the correlation between specific PRPF31 genotype and RP phenotype, suggesting that, except in cases of complete gene deletion or large-scale deletions, dominant negative effects contribute to phenotype as well as haploinsufficiency. This has important impacts on design of targeted therapies, particularly the feasibility of gene augmentation as a broad approach for treatment of PRPF31-associated RP. We discuss other opportunities for therapy, including antisense oligonucleotide therapy and gene-independent approaches and offer future perspectives on treatment of this form of RP.

Citation

Wheway, G., Douglas, A., Baralle, D., & Guillot, E. (2020). Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy. Experimental Eye Research, 192, Article 107950. https://doi.org/10.1016/j.exer.2020.107950

• Journal Article Type: Article
• Acceptance Date: Jan 27, 2020
• Online Publication Date: Jan 31, 2020
• Publication Date: Mar 1, 2020
• Deposit Date: Sep 25, 2020
• Publicly Available Date: Sep 25, 2020
• Journal: Experimental Eye Research
• Print ISSN: 0014-4835
• Electronic ISSN: 1096-0007
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 192
• Article Number: 107950
• DOI: https://doi.org/10.1016/j.exer.2020.107950
• Keywords: Ophthalmology; Sensory Systems; Cellular and Molecular Neuroscience
• Public URL: https://uwe-repository.worktribe.com/output/5919722
• Additional Information: This article is maintained by: Elsevier; Article Title: Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy; Journal Title: Experimental Eye Research; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.exer.2020.107950; Content Type: article; Copyright: © 2020 The Authors. Published by Elsevier Ltd.