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

Exp Eye Res. 2020 Mar:192:107950. doi: 10.1016/j.exer.2020.107950. Epub 2020 Jan 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • DNA Mutational Analysis
  • Electroretinography
  • Eye Proteins / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Therapy*
  • Humans
  • Male
  • Mutation / genetics*
  • Oligonucleotides, Antisense
  • Polymerase Chain Reaction
  • RNA Splicing
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / therapy*

Substances

  • Eye Proteins
  • Oligonucleotides, Antisense
  • PRPF31 protein, human