PRPF4 mutations cause autosomal dominant retinitis pigmentosa

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Abstract

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.

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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

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