Specific correction of a splice defect in brain by nutritional supplementation

Recent studies emphasize the importance of mRNA splicing in human genetic disease, as 20-30% of all disease-causing mutations are predicted to result in mRNA splicing defects. The plasticity of the mRNA splicing reaction has made these mutations attractive candidates for the development of therapeut...

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Published in:	Human molecular genetics Vol. 20; no. 21; pp. 4093 - 4101
Main Authors:	Shetty, Ranjit S., Gallagher, Cary S., Chen, Yei-Tsung, Hims, Matthew M., Mull, James, Leyne, Maire, Pickel, James, Kwok, David, Slaugenhaupt, Susan A.
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-11-2011
Subjects:	Alternative Splicing - drug effects Animals Biological and medical sciences Brain - drug effects Brain - metabolism Carrier Proteins - genetics Carrier Proteins - metabolism Cells, Cultured Diet Dietary Supplements Dose-Response Relationship, Drug Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Kinetin - administration & dosage Kinetin - pharmacology Mice Mice, Transgenic Molecular and cellular biology Neurons - drug effects Neurons - metabolism Genetics Splice Supplementation Splicing Central nervous system Encephalon
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Summary:	Recent studies emphasize the importance of mRNA splicing in human genetic disease, as 20-30% of all disease-causing mutations are predicted to result in mRNA splicing defects. The plasticity of the mRNA splicing reaction has made these mutations attractive candidates for the development of therapeutics. Familial dysautonomia (FD) is a severe neurodegenerative disorder, and all patients have an intronic IVS20+6T>C splice site mutation in the IKBKAP gene, which results in tissue-specific skipping of exon 20 and a corresponding reduction in ikappaB kinase complex associated protein (IKAP) levels. We created transgenic mouse lines using a human IKBKAP bacterial artificial chromosome (BAC) into which we inserted the IKBKAP splice mutation (FD BAC) and have shown that the transgenic mice exhibit the same tissue-specific aberrant splicing patterns as seen in FD patients. We have previously demonstrated that the plant cytokinin kinetin can significantly improve the production of wild-type IKBKAP transcripts in FD lymphoblast cell lines by improving exon inclusion. In this study, we tested the ability of kinetin to alter IKBKAP splicing in the transgenic mice carrying the FD BAC and show that it corrects IKBKAP splicing in all major tissues assayed, including the brain. The amount of wild-type IKBKAP mRNA and IKAP protein was significantly higher in the kinetin-treated mice. These exciting results prove that treatment of FD, as well as other mechanistically related splicing disorders, with kinetin holds great promise as a potential therapeutic aimed at increasing normal protein levels, which may, in turn, slow disease progression.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0964-6906 1460-2083
DOI:	10.1093/hmg/ddr333