title: Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.
abstract: Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Unité de Formation et de Recherche Médecine Site Nord Unité Pédagogique Médicale/IURC, Montpellier, France. christophe.beroud@igh.cnrs.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Béroud
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tuffery-Giraud
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.forename: Dalil
authors.initials: D
authors.lastname: Hamroun
authors.forename: Véronique
authors.initials: V
authors.lastname: Humbertclaude
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Moizard
authors.forename: Marie-Antoinette
authors.initials: MA
authors.lastname: Voelckel
authors.forename: Laurence Michel
authors.initials: LM
authors.lastname: Calemard
authors.forename: Pierre
authors.initials: P
authors.lastname: Boisseau
authors.forename: Martine
authors.initials: M
authors.lastname: Blayau
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.forename: Mireille
authors.initials: M
authors.lastname: Cossée
authors.forename: Michel
authors.initials: M
authors.lastname: Pagès
authors.forename: François
authors.initials: F
authors.lastname: Rivier
authors.forename: Olivier
authors.initials: O
authors.lastname: Danos
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018389:Codon, Nonsense; D019295:Computational Biology; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D006801:Humans; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy; D016376:Oligonucleotides, Antisense; D016366:Open Reading Frames; D010641:Phenotype; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; C484258:DMD protein, human; D016189:Dystrophin; D016376:Oligonucleotides, Antisense