%0 Journal Article
%1 10.1371/journal.pgen.1008690
%A Krooss, S
%A Werwitzke, S
%A Kopp, J
%A Rovai, A
%A Varnholt, D
%A Wachs, A S
%A Goyenvalle, A
%A Aarstma-Rus, A
%A Ott, M
%A Tiede, A
%A Langemeier, J
%A Bohne, J
%D 2020
%I Public Library of Science
%J PLOS Genet
%K 2020
%N 4
%P 1-20
%T Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B
%U https://doi.org/10.1371/journal.pgen.1008690
%V 16
%X Author summary The elucidation of the pathomechanisms of non-coding variants yields important insights into diseases as well as cellular processes causing the defect. Although these variants may account for the majority of phenotypic variation, only a minority of them can be explained mechanistically. The human coagulation factor 9 3’ UTR variant described here converts a non-essential sequence motif into a U1snRNP-binding site with deleterious effects on RNA 3’ end processing at the nearby poly(A) site. Poly(A) site suppression by U1snRNP was described before and it normally protects cellular mRNAs from premature termination. However, if misled by creation of a U1 site close the authentic poly(A) site as in the F9 3’ UTR, this nuclear surveillance mechanism results in the opposite. Since recognition by U1snRNP depends on sequence complementarity we were able to use antisense oligonucleotides to mask the mutant site and partially restored F9 mRNA levels. This antisense based strategy may be applicable to other variants in untranslated regions, which create deleterious binding sites for cellular proteins.