Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs.

Gorman, L; Suter, D; Emerick, V; Schümperli, Daniel; Kole, R (1998). Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 95(9), pp. 4929-4934. National Academy of Sciences NAS

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In several forms of beta-thalassemia, mutations in the second intron of the beta-globin gene create aberrant 5' splice sites and activate a common cryptic 3' splice site upstream. As a result, the thalassemic beta-globin pre-mRNAs are spliced almost exclusively via the aberrant splice sites leading to a deficiency of correctly spliced beta-globin mRNA and, consequently, beta-globin. We have designed a series of vectors that express modified U7 snRNAs containing sequences antisense to either the aberrant 5' or 3' splice sites in the IVS2-705 thalassemic pre-mRNA. Transient expression of modified U7 snRNAs in a HeLa cell line stably expressing the IVS2-705 beta-globin gene restored up to 65% of correct splicing in a sequence-specific and dose-dependent manner. Cell lines that stably coexpressed IVS2-705 pre-mRNA and appropriately modified U7 snRNA exhibited up to 55% of permanent restoration of correct splicing and expression of full-length beta-globin protein. This novel approach provides a potential alternative to gene replacement therapies.

Item Type:	Journal Article (Original Article)
Division/Institute:	08 Faculty of Science > Department of Biology > Institute of Cell Biology 08 Faculty of Science > Department of Biology > Institute of Cell Biology > RNA
UniBE Contributor:	Schümperli, Daniel
Subjects:	500 Science > 570 Life sciences; biology 500 Science
ISSN:	0027-8424
Publisher:	National Academy of Sciences NAS
Language:	English
Submitter:	Daniel Schümperli
Date Deposited:	11 Sep 2015 11:53
Last Modified:	05 Dec 2022 14:49
PubMed ID:	9560205
URI:	https://boris.unibe.ch/id/eprint/71625