Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation

Malka Nissim-Rafinia, Micha Aviram, Scott H. Randell, Liat Shushi, Efrat Ozeri, Ornit Chiba-Falek, Ofer Eidelman, Harvey B. Pollard, James R. Yankaskas, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


A significant fraction of disease-causing mutations affects pre-mRNA splicing. These mutations can generate both aberrant and correct transcripts, the level of which varies among different patients. An inverse correlation was found between this level and disease severity, suggesting a role for splicing regulation as a genetic modifier. Overexpression of splicing factors increased the level of correctly spliced RNA, transcribed from minigenes carrying disease-causing splicing mutations. However, whether this increase could restore the protein function was unknown. Here, we demonstrate that overexpression of Htra2-β1 and SC35 increases the level of normal cystic fibrosis transmembrane conductance regulator (CFTR) transcripts in cystic-fibrosis-derived epithelial cells carrying the 3849 + 10 kb C → T splicing mutation. This led to activation of the CFTR channel and restoration of its function. Restoration was also obtained by sodium butyrate, a histone deacetylase inhibitor, known to upregulate the expression of splicing factors. These results highlight the therapeutic potential of splicing modulation for genetic diseases caused by splicing mutations.

Original languageAmerican English
Pages (from-to)1071-1077
Number of pages7
JournalEMBO Reports
Issue number11
StatePublished - Nov 2004


  • Cystic fibrosis
  • Cystic fibrosis transmembrane conductance regulator functional restoration
  • Sodium butyrate
  • Splicing factors
  • Splicing pattern modulation


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