Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence

Marquis, Julien; Meyer, Kathrin; Angehrn, Larissa; Kämpfer, Sacha; Rothen-Rutishauser, Barbara; Schümperli, Daniel (2007). Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence. Molecular therapy, 15(8), pp. 1479-1486. New York, N.Y.: Nature Publishing Group 10.1038/sj.mt.6300200

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Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival of motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, is only an incomplete substitute, because a single nucleotide difference impairs the inclusion of its seventh exon in the messenger RNA (mRNA). This splicing defect can be corrected (transiently) by specially designed oligonucleotides. Here we have developed a more permanent correction strategy based on bifunctional U7 small nuclear RNAs (snRNAs). These carry both an antisense sequence that allows specific binding to exon 7 and a splicing enhancer sequence that will improve the recognition of the targeted exon. When expression cassettes for these RNAs are stably introduced into cells, the U7 snRNAs become incorporated into small nuclear ribonucleoprotein (snRNP) particles that will induce a durable splicing correction. We have optimized this strategy to the point that virtually all SMN2 pre-mRNA becomes correctly spliced. In fibroblasts from an SMA patient, this approach induces a prolonged restoration of SMN protein and ensures its correct localization to discrete nuclear foci (gems).

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Department of Clinical Research (DCR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Rothen-Rutishauser, Barbara and Schümperli, Daniel

ISSN:

1525-0016

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:56

Last Modified:

06 Dec 2013 13:47

Publisher DOI:

10.1038/sj.mt.6300200

PubMed ID:

17505471

Web of Science ID:

000248412900012

URI:

https://boris.unibe.ch/id/eprint/23723 (FactScience: 43774)

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