title: Chemical treatment enhances skipping of a mutated exon in the dystrophin gene.
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.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nishida
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kataoka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Mariko
authors.initials: M
authors.lastname: Yagi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Awano
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ota
authors.forename: Kyoko
authors.initials: K
authors.lastname: Itoh
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D002460:Cell Line; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense / Q000187:drug effects*; D016189:Dystrophin / Q000096:biosynthesis / Q000235:genetics*; D005091:Exons; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D017354:Point Mutation; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D018389:Codon, Nonsense; D016189:Dystrophin; D012333:RNA, Messenger; C487497:TG 003; D013844:Thiazoles