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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-5223

Tanner, G; Glaus, E; Barthelmes, D; Ader, M; Fleischhauer, J; Pagani, F; Berger, W; Neidhardt, J (2009). Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA. Human Mutation, 30(2):255-263.

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Retinitis pigmentosa (RP) is a degenerative retinopathy leading to visual impairment in more than 1.5 million patients worldwide. Splice site (SS) mutations cause various diseases including RP. Most exonic donor splice-site (DS) mutations are reported at the last nucleotide of an exon and over 95% of them are predicted to result in missplicing. A novel human mutation at the last nucleotide of exon 4 in rhodopsin (RHO, c.936G>A) is shown to generate two misspliced transcripts in COS 7 cells and retinal explants. One of these transcripts skips exon 4 whereas the other activates a cryptic DS. Both are predicted to result in truncated RHO, explaining the pathogenic mechanism underlying the patient's RP phenotype. U1 snRNA-mediated DS recognition is a key step in the splicing process. As a therapeutic strategy, U1 snRNAs were adapted to the novel RHO mutation and tested for its potential to reverse missplicing. The rescue efficiency for misspliced transcripts of RHO was examined by quantitative RT-PCR. Using mutation-adapted U1 snRNA, we observed significantly reduced exon skipping that reached wild-type levels. Nevertheless, activation of the cryptic splice site (CS) was still detected. To test the feasibility of the strategy for mutations that only cause exon skipping, we inactivated the CS. Indeed, adapted U1 snRNA was able to rescue almost 90% of misspliced transcripts. This study shows that modified U1 snRNAs constitute a promising therapeutic strategy to treat DS mutations. Our findings have implications for various diseases caused by similar mutations.


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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
04 Faculty of Medicine > Institute of Medical Molecular Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:February 2009
Deposited On:20 Jan 2009 17:10
Last Modified:05 Apr 2016 12:33
Publisher DOI:10.1002/humu.20861
PubMed ID:18837008

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