Regeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de Olavide, Avda. Americo Vespucio 24, 41092, Seville, Spain.
Present Address: Center for Biomedical Research (CBMR), University of Algarve, 8800-139, Faro, Portugal.
Mol Med. 2019 Dec 31;26(1):1. doi: 10.1186/s10020-019-0124-z.
Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease.
In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene.
We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus.
Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.
前体 mRNA 剪接因子 PRPF31 的突变可导致色素性视网膜炎（RP）。尽管确切的疾病机制尚不清楚，但据推测杂合不足可能与疾病的病理生理学有关。
在本研究中，我们分析了含有 Prpf31 基因 p.A216P 突变的小鼠模型。
我们发现突变的 Prpf31 蛋白在视网膜色素上皮中产生细胞质聚集体，并降低核内这种剪接因子的蛋白水平。此外，当突变蛋白在体外过表达时，正常蛋白被募集到不溶性聚集体中。作为对蛋白聚集的反应，Hspa4l 过表达。该伴侣蛋白 HSP70 家族的成员可能有助于突变蛋白的正确折叠和溶解，使其易位到核内。
我们的数据表明，PRPF31 突变导致的视网膜变性涉及杂合不足和显性负效应机制。HSP70 的过表达可能是治疗 PRPF31 突变引起的视网膜变性的新治疗靶点。
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