期刊
EMBO JOURNAL
卷 20, 期 7, 页码 1774-1784出版社
WILEY
DOI: 10.1093/emboj/20.7.1774
关键词
alternative splicing; CFTR exon 9; cystic fibrosis; SF2; ASF; TDP-43
资金
- Telethon [E.1038] Funding Source: Medline
Alternative splicing of human cystic fibrosis transmembrane conductance regulator (CFTR) exon 9 is regulated by a combination of cis-acting elements distributed through the exon and both flanking introns (IVS8 and IVS9). Several studies have identified in the IVS8 intron 3' splice site a regulatory element that is composed of a polymorphic (TG)m(T)n repeated sequence. At present, no cellular factors have been identified that recognize this element. We have identified TDP-43, a nuclear protein not previously described to bind RNA, as the factor binding specifically to the (TG)m sequence. Transient TDP-43 overexpression in Hep3B cells results in an increase in exon 9 skipping. This effect is more pronounced with concomitant overexpression of SR proteins. Antisense inhibition of endogenous TDP-43 expression results in increased inclusion of exon 9, providing a new therapeutic target to correct aberrant splicing of exon 9 in CF patients. The: clinical and biological relevance of this finding in vivo is demonstrated by our characterization of a CF patient carrying a TG10T9(Delta F508)/ TG13T3(wt) genotype leading to a disease-causing high proportion of exon 9 skipping.
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