Splicing modulation as a modifier of the CFTR function.

Malka Nissim-Rafinia*, Batsheva Kerem

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


A significant fraction of CF-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. Subsequent studies showed that overexpression of splicing factors modulated the level of correctly spliced RNA, transcribed from minigenes carrying CF-causing splicing mutations. Overexpression of splicing factors also modulated the level of normal CFTR transcripts, transcribed from the endogenous CFTR allele carrying splicing mutations, in CF-derived epithelial cells. Several of the factors promoted higher level of correct CFTR transcripts. The increased level of normal transcripts 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 up-regulate the expression of splicing factors. These results highlight the role of the splicing machinery as a modifier of disease severity in patients carrying splicing mutations and shed a new light on the therapeutic potential of splicing modulation for genetic diseases caused by splicing mutations.

Original languageAmerican English
Pages (from-to)233-254
Number of pages22
JournalProgress in molecular and subcellular biology
StatePublished - 2006


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