Journal article
Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45
Annals of neurology, Vol.77(4), pp.668-674
04/2015
DOI: 10.1002/ana.24365
PMCID: PMC4376581
PMID: 25612243
Abstract
Objective
Exon‐skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre‐mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion—exon 45 (Δ45)—may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients.
Methods
Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in‐frame deletions.
Results
As expected, deletions of either exons 45 to 47 (Δ45–47) or exons 45 to 48 (Δ45–48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45–46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in‐frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44–45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype.
Interpretation
The observation that Δ45–46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46–48) are better potential therapies than skipping of exon 46 alone. Ann Neurol 2015 Ann Neurol 2015;77:668–674
Details
- Title: Subtitle
- Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45
- Creators
- Andrew R Findlay - Center for Gene Therapy, Nationwide Children's HospitalNicolas Wein - Center for Gene Therapy, Nationwide Children's HospitalYuuki Kaminoh - Center for Gene Therapy, Nationwide Children's HospitalLaura E Taylor - Center for Gene Therapy, Nationwide Children's HospitalDiane M Dunn - University of Utah School of MedicineJerry R Mendell - Ohio State UniversityWendy M King - Ohio State UniversityAlan Pestronk - Washington University at St LouisJulaine M Florence - Washington University at St LouisKatherine D Mathews - University of Iowa Carver College of MedicineRichard S Finkel - Nemours Children's HospitalKathryn J Swoboda - University of Utah School of MedicineMichael T Howard - University of Utah School of MedicineJohn W Day - University of MinnesotaCraig McDonald - University of CaliforniaAurélie Nicolas - Rennes Institute of Genetics and Development, National Center for Scientific ResearchElisabeth Rumeur - Rennes Institute of Genetics and Development, National Center for Scientific ResearchRobert B Weiss - University of Utah School of MedicineKevin M Flanigan - Ohio State University
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.77(4), pp.668-674
- DOI
- 10.1002/ana.24365
- PMID
- 25612243
- PMCID
- PMC4376581
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Number of pages
- 7
- Grant note
- NIH National Institute of Neurologic Disorders and Stroke (R01 NS043264) Association Française contre les Myopathies (16810)
- Language
- English
- Date published
- 04/2015
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984020502102771
Metrics
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