Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 4 429-436
DOI: 10.1093/hmg/ddh046
Rescue of a human mRNA splicing defect by the plant cytokinin kinetin
1Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Charlestown, MA 02129, USA, 2Harvard Institute of Human Genetics, Harvard Medical School, Boston, MA 02115, USA and 3Department of Pediatrics, New York University Medical School, New York, NY 10021, USA
Received October 16, 2003; Accepted December 17, 2003
The defective splicing of pre-mRNA is a major cause of human disease. Exon skipping is a common result of splice mutations and has been reported in a wide variety of genetic disorders, yet the underlying mechanism is poorly understood. Often, such mutations are incompletely penetrant, and low levels of normal transcript and protein are maintained. Familial dysautonomia (FD) is caused by mutations in IKBKAP, and all cases described to date involve an intron 20 mutation that results in a unique pattern of tissue-specific exon skipping. Accurate splicing of the mutant IKBKAP allele is particularly inefficient in the nervous system. Here we show that treatment with the plant cytokinin kinetin alters splicing of IKBKAP. Kinetin significantly increases inclusion of exon 20 from the endogenous gene, as well as from an IKBKAP minigene. By contrast the drug does not enhance inclusion of alternatively spliced exon 31 in MYO5A. Benzyladenine, the most closely related cytokinin, showed a similar but less dramatic effect. Our findings reveal a remarkable impact on splicing fidelity by these small molecules, which therefore provide new tools for the dissection of mechanisms controlling tissue-specific pre-mRNA splicing. Further, kinetin should be explored as a treatment for increasing the level of normal IKAP in FD, and for other splicing disorders that may share a similar mechanism.
* To whom correspondence should be addressed at: NRB Building Room 160C, 4 Blackfan Circle, Boston, MA 02115, USA. Tel: +1 6175254558; Fax: +1 6175254533; Email: susan_slaugenhaupt{at}hms.harvard.edu
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