Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy. (March 2020)

• Record Type: Journal Article
• Authors: Wheway, Gabrielle; Douglas, Andrew; Baralle, Diana; Guillot, Elsa
• Is Part Of: Experimental eye research. Volume 192(2020)
• Publication Date: 2020-03
• Subjects: Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2020.107950
• Languages: English
• ISSNs: 0014-4835

Abstract

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. Highlights: PRPF31 is the second most common cause of autosomal dominant retinitis pigmentosa and a potential target for gene therapy. We present all reported pathogenic variants in PRPF31 as a resource for clinicians, diagnostic genetics labs, and researchers. Genotype-phenotype correlations suggest that, dominant negative effects contribute to disease in addition to haploinsufficiency. This finding has important impacts on the suitability of gene augmentation approaches across all mutation types. This finding may aid prognosis of disease in PRPF31 -associated RP patients.