EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia

Sylvia L. Anderson, Jinsong Qiu and Berish Y. Rubin^,

Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY, USA

Received 31 July 2003.  Available online 13 September 2003.
 

Abstract

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disorder. The most prevalent causative mutation is a T → C transition in a donor splice site of the IKBKAP transcript, resulting in aberrant splicing and a truncated protein. The mutation’s position and leaky nature suggested that its impact might be moderated by altering the level of splice-regulating proteins. The reported ability of (−)-epigallocatechin gallate (EGCG), a polyphenol, to down-regulate the expression of hnRNP A2/B1, a trans-activating factor that encourages the use of intron-distal 5^′ splice sites, prompted an evaluation of its effect on the IKBKAP transcript in FD-derived cells. EGCG reduces the level of hnRNP A2/B1 and increases the amounts of the wild-type IKBKAP-encoded transcript and functional protein. Combined treatment of cells with EGCG and tocotrienol, which upregulates IKBKAP transcription, results in a synergistic production of the functional gene product. These findings suggest the possible use of EGCG as a therapeutic modality for individuals with FD.