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Abstract
BackgroundMutations 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.MethodsIn this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene.ResultsWe 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.ConclusionsOur 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.
Highlights
Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP)
Mutations in PRPF31 have been described as the second most common cause of autosomal dominant RP known as RP11 (Vithana et al, 2001; AlMaghtheh et al, 1998; Rose et al, 2016) and, PRPF31 is necessary for pre-mRNA splicing in every cell, adRP is the only clinical entity associated with these mutations
Small round, white-yellowish, non-confluent, scattered lesions were observed throughout the retina of Prpf31A216P/+ mice like drusenoid deposits (Fig. 1e-h)
Summary
Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Pre-mRNA splicing is a general cellular function crucial for the expression of eukaryotic transcripts. It is catalyzed by the spliceosome, a large ribonucleoprotein complex composed of five small nuclear ribonucleoprotein complexes (Ruzickova & Stanek, 2017). Mutations in PRPF31 have been described as the second most common cause of autosomal dominant RP (adRP) known as RP11 (Vithana et al, 2001; AlMaghtheh et al, 1998; Rose et al, 2016) and, PRPF31 is necessary for pre-mRNA splicing in every cell, adRP is the only clinical entity associated with these mutations
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