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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.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Brief Report

U1-snRNA–mediated rescue of mRNA processing in severe factor VII deficiency

Mirko Pinotti1, Lara Rizzotto1, Dario Balestra1, Marzena Anna Lewandowska2, Nicola Cavallari1, Giovanna Marchetti1, Francesco Bernardi1, and Franco Pagani2

1 Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara; and 2 International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

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 neighboring 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 37-bp 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.


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