Retinitis pigmentosa (RP), a disease characterized by progressive loss of photoreceptors, exhibits significant genetic heterogeneity. Several genes associated with U4/U6-U5 triple small nuclear ribonucleoprotein (trisnRNP) complex of the spliceosome have been implicated in autosomal dominant RP (adRP). HPrp4, encoded by PRPF4, regulates the stability of U4/U6 di-snRNP, which is essential for continuous splicing. Here, we identified two heterozygous variants in PRPF4, including c.-114_-97del in a simplex RP patient and c.C944T (p.Pro315Leu), which co-segregates with disease phenotype in a family with adRP. Both variants were absent in 400 unrelated controls. The c.-114_-97del, predicted to affect two transcription factor binding sites, was shown to down-regulate the promoter activity of PRPF4 by a luciferase assay, and was associated with a significant reduction of PRPF4 expression in the blood cells of the patient. In fibroblasts from an affected individual with the p.Pro315Leu variant, the expression levels of several tri-snRNP components, including PRPF4 itself, were up-regulated, with altered expression pattern of SC35, a spliceosome marker. The same alterations were also observed in cells over expressing hPrp4Pro315Leu, suggesting that they arose as a compensatory response toacompromised splicingmechanismcausedbyhPrp4dysfunction. Further, over expression ofhPrp4Pro315Leu, but nothPrp4WT, triggered systemic deformities in wild-type zebrafishembryoswith the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced.Weconclude that mutations ofPRPF4 causeRPvia haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP. © The Author 2014. Published by Oxford University Press. All rights reserved. Published by Oxford University Press. All rights reserved.
Chen, X., Liu, Y., Sheng, X., Tam, P. O. S., Zhao, K., Chen, X., … Zhao, C. (2014). PRPF4 mutations cause autosomal dominant retinitis pigmentosa. Human Molecular Genetics, 23(11), 2926–2939. https://doi.org/10.1093/hmg/ddu005