title: Nutraceutical-mediated restoration of wild-type levels of IKBKAP-encoded IKAP protein in familial dysautonomia-derived cells.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY10458, USA.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Anderson
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Sturm
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Schwartz
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Peters
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Sullivan
authors.forename: Berish Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D019587:Dietary Supplements; D004357:Drug Synergism; D004402:Dysautonomia, Familial / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035602:Transcriptional Elongation Factors; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D007529:Isoflavones; D035602:Transcriptional Elongation Factors; C004742:daidzein; D002392:Catechin; C045651:epigallocatechin gallate; D019833:Genistein; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase