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

Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy
Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy
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.
0014-4835
1-21
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Douglas, Andrew
2c789ec4-a222-43bc-a040-522ca64fea42
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Guillot, Elsa
41a5e568-885c-49a8-b672-08586b975484
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Douglas, Andrew
2c789ec4-a222-43bc-a040-522ca64fea42
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Guillot, Elsa
41a5e568-885c-49a8-b672-08586b975484

Wheway, Gabrielle, Douglas, Andrew, Baralle, Diana and Guillot, Elsa (2020) Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy. Experimental Eye Research, 192, 1-21, [107950]. (doi:10.1016/j.exer.2020.107950).

Record type: Review

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.

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YEXER_2019_602_Revision 1_V0 - Accepted Manuscript
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Accepted/In Press date: 27 January 2020
e-pub ahead of print date: 31 January 2020
Published date: March 2020

Identifiers

Local EPrints ID: 438846
URI: http://eprints.soton.ac.uk/id/eprint/438846
ISSN: 0014-4835
PURE UUID: 2cb29c91-cbdc-44ab-9e8a-5c27511c867e
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for Andrew Douglas: ORCID iD orcid.org/0000-0001-5154-6714
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

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Date deposited: 25 Mar 2020 17:31
Last modified: 28 Apr 2022 05:13

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Contributors

Author: Andrew Douglas ORCID iD
Author: Diana Baralle ORCID iD
Author: Elsa Guillot

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