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Restoration of the cystic fibrosis transmembrane conductance regulator function by splicing modulation
Author(s) -
NissimRafinia Malka,
Aviram Micha,
Randell Scott H,
Shushi Liat,
Ozeri Efrat,
ChibaFalek Ornit,
Eidelman Ofer,
Pollard Harvey B,
Yankaskas James R,
Kerem Batsheva
Publication year - 2004
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400273
Subject(s) - hebrew , chapel , library science , medicine , cystic fibrosis transmembrane conductance regulator , classics , history , art history , cystic fibrosis , computer science
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.