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

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

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.

Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Schematic representation of the first four steps of pre-mRNA splicing by the major spliceosome, with PRPF31 shown in red. In step 1, U1snRNP recognises and binds the splice donor site (the 5′ splice site). In step 2, binding of U1snRNP to the splice donor site promotes the binding of U2snRNP to the branch site. Independently of this, the U4/U6.U5 tri-snRNP forms in the cell. In step 3, the U4/U6.U5 tri-snRNP is recruited to the pre-mRNA, where U6snRNP replaces U1snRNP. This forms the catalytically active spliceosome, which in step 4 cuts away the intron and joins the exons through two transesterification reactions. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
Schematic representation of the protein and cDNA structure of PRPF31, showing major structural domains encoded by each exon.
Fig. 3
Fig. 3
Schematic representation PRPF31 gene, with all reported pathogenic variants labelled above, and total numbers of variants in each intron and exon displayed as a bar chart below. This shows that exons 7 and 8 are most enriched for pathogenic variants.
Fig. 4
Fig. 4
(a) Box and whisker plots showing upper and lower limits, median and interquartile range of reported age of onset of RP patients with different types of variant in PRPF31 (b) Box and whisker plots showing upper and lower limits, median and interquartile range of reported age of diagnosis of RP patients with different types of variant in PRPF31.

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