Chemical treatment enhances skipping of a mutated exon in the dystrophin gene

Atsushi Nishida, Naoyuki Kataoka, Yasuhiro Takeshima, Mariko Yagi, Hiroyuki Awano, Mitsunori Ota, Kyoko Itoh, Masatoshi Hagiwara () and Masafumi Matsuo ()
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Atsushi Nishida: Kobe University Graduate School of Medicine
Naoyuki Kataoka: Medical Top Track Program, Medical Research Institute, Tokyo Dental and Medical University
Yasuhiro Takeshima: Kobe University Graduate School of Medicine
Mariko Yagi: Kobe University Graduate School of Medicine
Hiroyuki Awano: Kobe University Graduate School of Medicine
Mitsunori Ota: Kobe University Graduate School of Medicine
Kyoko Itoh: Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Masatoshi Hagiwara: Tokyo Dental and Medical University
Masafumi Matsuo: Kobe University Graduate School of Medicine

Nature Communications, 2011, vol. 2, issue 1, 1-8

Abstract: Abstract Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon, a small amount of internally deleted, but functional, dystrophin protein is produced in the patient cells. An analysis of the mRNA reveals that the mutation promotes exon skipping and restores the open reading frame of dystrophin. Presumably, the mutation disrupts an exonic splicing enhancer and creates an exonic splicing silencer. Therefore, we searched for small chemicals that enhance exon skipping, and found that TG003 promotes the skipping of exon 31 in the endogenous dystrophin gene in a dose-dependent manner and increases the production of the dystrophin protein in the patient's cells.

Date: 2011
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DOI: 10.1038/ncomms1306

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