title: EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia.
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.
authors.affiliation: Laboratory for Familial Dysautonomia Research, Department of Biological Sciences, Fordham University, Bronx, NY, USA.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Anderson
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.forename: Berish Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D004402:Dysautonomia, Familial / Q000235:genetics* / Q000378:metabolism; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D024508:Tocotrienols / Q000494:pharmacology; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D024508:Tocotrienols; D035602:Transcriptional Elongation Factors; D002392:Catechin; C045651:epigallocatechin gallate