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: Sylvia L Anderson, Jinsong Qiu, Berish Y Rubin
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 310 Issue 2 Pg. 627-33 (Oct 17 2003) ISSN: 0006-291X [Print] United States
• PMID: 14521957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Elp1 protein, human
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• RNA, Messenger
• Tocotrienols
• Transcriptional Elongation Factors
• Catechin
• epigallocatechin gallate

Topics

• Base Sequence
• Carrier Proteins (genetics, metabolism)
• Catechin (analogs & derivatives, pharmacology)
• Cell Line
• Drug Synergism
• Dysautonomia, Familial (genetics, metabolism)
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (genetics, metabolism)
• Humans
• Molecular Sequence Data
• Mutation
• RNA Splicing (drug effects)
• RNA, Messenger (chemistry, metabolism)
• Tocotrienols (pharmacology)
• Transcriptional Elongation Factors