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EnglishSmall 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.
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| Titolo: | U1snRNA-mediated rescue of mRNA processing in severe factor VII deficiency |
| Autori: | |
| Data di pubblicazione: | 2008 |
| Rivista: | |
| Abstract: | 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. |
| Handle: | http://hdl.handle.net/11392/520017 |
| Appare nelle tipologie: | 03.1 Articolo su rivista |
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