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U1snRNA-mediated rescue of mRNA processing in severe factor VII deficiency

By Mirko Pinotti, Lara Rizzotto, Dario Balestra, Marzena Anna Lewandowska, Nicola Cavallari, Giovanna Marchetti, Francesco Bernardi and Franco Pagani


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.\ud 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

Topics: Factor VII deficiency, mRNA processing, rescue, modified snRNA, correction approaches
Year: 2008
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