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.
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.
Béroud
Christophe
C
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
Tuffery-Giraud
Sylvie
S
Matsuo
Masafumi
M
Hamroun
Dalil
D
Humbertclaude
Véronique
V
Monnier
Nicole
N
Moizard
Marie-Pierre
MP
Voelckel
Marie-Antoinette
MA
Calemard
Laurence Michel
LM
Boisseau
Pierre
P
Blayau
Martine
M
Philippe
Christophe
C
Cossée
Mireille
M
Pagès
Michel
M
Rivier
François
F
Danos
Olivier
O
Garcia
Luis
L
Claustres
Mireille
M
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
D018389:Codon, Nonsense; C484258:DMD protein, human; D016189:Dystrophin; D016376:Oligonucleotides, Antisense