Clinical Phenotypes As Predictors of the Outcome of Skipping Around DMD Exon 45

Overview

Journal Ann Neurol

Specialty Neurology

Date 2015 Jan 23

PMID 25612243

Citations 27

Authors

Andrew R Findlay

Nicolas Wein

Yuuki Kaminoh

Laura E Taylor

Diane M Dunn

Jerry R Mendell

Wendy M King

Alan Pestronk

Julaine M Florence

Katherine D Mathews

Richard S Finkel

Kathryn J Swoboda

Michael T Howard

John W Day

Craig McDonald

Aurelie Nicolas

Elisabeth Le Rumeur

Robert B Weiss

Kevin M Flanigan

Affiliations

Soon will be listed here.

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.

Citing Articles

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A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular Dysfunctions Found by Whole Exome Sequencing and Analyses in an Iranian Family.

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Exon 44 skipping in Duchenne muscular dystrophy: NS-089/NCNP-02, a dual-targeting antisense oligonucleotide.

Watanabe N, Tone Y, Nagata T, Masuda S, Saito T, Motohashi N Mol Ther Nucleic Acids. 2023; 34:102034.

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Targeting Duchenne muscular dystrophy by skipping DMD exon 45 with base editors.

Gapinske M, Winter J, Swami D, Gapinske L, Woods W, Shirguppe S Mol Ther Nucleic Acids. 2023; 33:572-586.

PMID: 37637209 PMC: 10448430. DOI: 10.1016/j.omtn.2023.07.029.

Systemic administration of the antisense oligonucleotide NS-089/NCNP-02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: Study protocol for a phase I/II clinical trial.

Ishizuka T, Komaki H, Asahina Y, Nakamura H, Motohashi N, Takeshita E Neuropsychopharmacol Rep. 2023; 43(2):277-286.

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