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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2681-2684. Prepublished online as a Blood First Edition Paper on December 21, 2007; DOI 10.1182/blood-2007-10-117440. This Article Full Text (PDF) All Versions of this Article: blood-2007-10-117440v1 111/5/2681    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pinotti, M. Articles by Pagani, F. Search for Related Content PubMed PubMed Citation Articles by Pinotti, M. Articles by Pagani, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 9, 2007 Accepted December 18, 2007 U1snRNA-mediated rescue of mRNA processing in severe factor VII deficiency Mirko Pinotti*, Lara Rizzotto, Dario Balestra, Marzena Anna Lewandowska, Nicola Cavallari, Giovanna Marchetti, Francesco Bernardi, and Franco Pagani Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy International Centre for Genetic Engineering and Biotechnology, Trieste, Italy * Corresponding author; email: pnm{at}unife.it. Small nuclear U1-RNAs (snRNAs), the spliceosome components selectively recognizing donor splice sites (5'ss), were engineered to restore correct mRNA processing in a cellular model of severe coagulation factor VII (FVII) deficiency, caused by the IVS7 9726+5g/a change. Three U1-snRNAs, complementary to the mutated 5’ss (U1+5a) or to neighbouring sequences, were expressed with FVII minigenes in a hepatoma cell line. The U1-snRNAs reduced from 80% to 40% the exon 7 skipping, thus increasing exon definition. The U1+5a construct also dramatically increased recognition of the correct 5'ss over the 37bp-downstream cryptic site preferentially activated by the mutation, thus inducing appreciable synthesis of normal transcripts (from barely detectable to 50%). This effect, which was dose-dependent, clearly demonstrated that impaired recognition by the U1-snRNA was the mechanism responsible for FVII deficiency. These findings suggest compensatory U1-snRNAs as therapeutic tools in coagulation factor deficiencies caused by mutations at 5'ss, a frequent cause of severe defects. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Pinotti, D. Balestra, L. Rizzotto, I. Maestri, F. Pagani, and F. Bernardi Rescue of coagulation factor VII function by the U1+5A snRNA Blood, June 18, 2009; 113(25): 6461 - 6464. [Abstract] [Full Text] [PDF]

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