Scope: The reported ability to modulate the production of the wild-type transcript in cells bearing the splice-altering familial dysautonomia (FD)-causing mutation in the IKBKAP gene prompted an evaluation of the impact of commonly consumed nutraceuticals on the splicing of this transcript.
Methods and results: Screening efforts revealed the ability of the isoflavones, genistein, and daidzein, to impact splicing and increase the production of the wild-type, exon-20-containing, transcript, and the full-length IKBKAP-encoded IΚB kinase complex associated protein(IKAP) in FD-derived cells. Genistein was also found to impact splicing in neuronal cells, a cell type profoundly impacted by FD. The simultaneous exposure of FD-derived cells to genistein and epigallocatechin gallate (EGCG) resulted in the almost exclusive production of the exon-20-containing transcript and the production of wild-type amounts of IKAP protein.
Conclusion: This study represents the first demonstration that the isoflavones, genistein and daidzein, possess splice-altering capabilities and that simultaneous treatment with genistein and EGCG reverses the splice-altering impact of the FD-causing mutation. These findings support the clinical evaluation of the therapeutic impact of the combined administration of these two commonly consumed nutraceuticals on this patient population and suggest a broader evaluation of the impact of these nutraceuticals on the in vivo RNA splicing process.
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.