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Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping.
Hum Mutat. 2009 Jan; 30(1):22-8.HM

Abstract

Out of three mutations in the dystrophin gene that cause Duchenne muscular dystrophy (DMD), the most common, serious childhood muscle wasting disease, two are genomic deletions of one or more exons that disrupt the reading frame. Specific removal of an exon flanking a genomic deletion using antisense oligonucleotide intervention during pre-RNA processing can restore the reading frame and could potentially reduce disease severity. We describe a rare dystrophin gene rearrangement; inversion of approximately 28 kb, flanked by a 10-bp duplication and an 11-kb deletion, which led to the omission of exons 49 and 50 from the mature mRNA and the variable inclusion of several pseudoexons. In vitro transfection of cultured patient cells with antisense oligonucleotides directed at exon 51 induced efficient removal of that exon, as well as one of the more commonly included pseudoexons, suggesting closely coordinated splicing of these exons. Surprisingly, several antisense oligonucleotides (AOs) directed at this pseudoexon had no detectable effect on the splicing pattern, while all AOs directed at the other predominant pseudoexon efficiently excised that target. Antisense oligomers targeting dystrophin exon 51 for removal are currently undergoing clinical trials. Despite the unique nature of the dystrophin gene rearrangement described here, a personalized multiexon skipping treatment is applicable and includes one compound entering clinical trials for DMD.

Authors+Show Affiliations

Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18570328

Citation

Madden, Heidi R., et al. "Characterization of a Complex Duchenne Muscular Dystrophy-causing Dystrophin Gene Inversion and Restoration of the Reading Frame By Induced Exon Skipping." Human Mutation, vol. 30, no. 1, 2009, pp. 22-8.
Madden HR, Fletcher S, Davis MR, et al. Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. Hum Mutat. 2009;30(1):22-8.
Madden, H. R., Fletcher, S., Davis, M. R., & Wilton, S. D. (2009). Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. Human Mutation, 30(1), 22-8. https://doi.org/10.1002/humu.20806
Madden HR, et al. Characterization of a Complex Duchenne Muscular Dystrophy-causing Dystrophin Gene Inversion and Restoration of the Reading Frame By Induced Exon Skipping. Hum Mutat. 2009;30(1):22-8. PubMed PMID: 18570328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. AU - Madden,Heidi R, AU - Fletcher,Sue, AU - Davis,Mark R, AU - Wilton,Steve D, PY - 2008/6/24/pubmed PY - 2009/3/18/medline PY - 2008/6/24/entrez SP - 22 EP - 8 JF - Human mutation JO - Hum Mutat VL - 30 IS - 1 N2 - Out of three mutations in the dystrophin gene that cause Duchenne muscular dystrophy (DMD), the most common, serious childhood muscle wasting disease, two are genomic deletions of one or more exons that disrupt the reading frame. Specific removal of an exon flanking a genomic deletion using antisense oligonucleotide intervention during pre-RNA processing can restore the reading frame and could potentially reduce disease severity. We describe a rare dystrophin gene rearrangement; inversion of approximately 28 kb, flanked by a 10-bp duplication and an 11-kb deletion, which led to the omission of exons 49 and 50 from the mature mRNA and the variable inclusion of several pseudoexons. In vitro transfection of cultured patient cells with antisense oligonucleotides directed at exon 51 induced efficient removal of that exon, as well as one of the more commonly included pseudoexons, suggesting closely coordinated splicing of these exons. Surprisingly, several antisense oligonucleotides (AOs) directed at this pseudoexon had no detectable effect on the splicing pattern, while all AOs directed at the other predominant pseudoexon efficiently excised that target. Antisense oligomers targeting dystrophin exon 51 for removal are currently undergoing clinical trials. Despite the unique nature of the dystrophin gene rearrangement described here, a personalized multiexon skipping treatment is applicable and includes one compound entering clinical trials for DMD. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/18570328/Characterization_of_a_complex_Duchenne_muscular_dystrophy_causing_dystrophin_gene_inversion_and_restoration_of_the_reading_frame_by_induced_exon_skipping_ DB - PRIME DP - Unbound Medicine ER -