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.

中文翻译：

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PRPF31 的突变谱、视网膜色素变性的基因型-表型相关性以及治疗机会。

前信使 RNA (pre-mRNA) 剪接因子 31、PRPF31 中的致病变异是大多数人群中常染色体显性遗传性色素性视网膜炎 (adRP) 的第二常见遗传原因。这仍然是一种完全无法治疗和无法治愈的失明形式，并且很难预测疾病的临床过程。为了设计合适的靶向治疗，需要对这种疾病的遗传学和分子机制有透彻的了解。在这里，我们介绍了 PRPF31 基因和 PRPF31 蛋白的结构、目前对 PRPF31 蛋白功能的理解以及所有报道的 PRPF31 临床相关变体的全谱。我们描述了特定 PRPF31 基因型和 RP 表型之间的相关性，这表明，除了完全基因缺失或大规模缺失的情况外，显性负效应导致表型以及单倍体不足。这对靶向治疗的设计具有重要影响，特别是基因增强作为治疗 PRPF31 相关 RP 的广泛方法的可行性。我们讨论了其他治疗机会，包括反义寡核苷酸治疗和基因独立方法，并提供了治疗这种形式的 RP 的未来前景。