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 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.
journal_name
Bloodjournal_title
Bloodauthors
Pinotti M,Rizzotto L,Balestra D,Lewandowska MA,Cavallari N,Marchetti G,Bernardi F,Pagani Fdoi
10.1182/blood-2007-10-117440subject
Has Abstractpub_date
2008-03-01 00:00:00pages
2681-4issue
5eissn
0006-4971issn
1528-0020pii
blood-2007-10-117440journal_volume
111pub_type
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