Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45

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 was analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions. Results As expected, deletions of either exons 45-47 (Δ45–47) or exons 45-48 (Δ45-48) result in BMD in 97% (36/37) of subjects. Unexpectedly, deletion of exons 45-46 (Δ45-46) is associated with the more severe DMD phenotype in 4/4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44-45 (Δ44-45) were found within the UDP 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 either exon 44 or multi-exon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone.

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

“…Indeed, the central domain has been until now considered as a monotonous rod-shaped domain which could be internally truncated without dramatic functional effects (2,15). However, the effects of in-frame mutations involving the central domain could be more severe than expected from the Monaco rule (16,17). Therefore, it is crucial to understand the molecular causes of the severity of certain inframe mutations to anticipate future therapies.…”

Recent advances in the management of Duchenne muscular dystrophy

“…However, by skipping the deleted or duplicated exon, the out-of-frame mutation is turned into an in-frame mutation. Dystrophin expression can therefore continue at a reduced level, which results in the milder Becker muscular dystrophy 43 44. Drisapersen is an AON that causes skipping of exon 51, which is a therapeutic strategy applicable to ∼13% of boys with DMD.…”

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

“…In the two examples here in Figure 5, two BMD-like deletions may be produced using the same drug in different patients. However, the deletion 45-46 has been recently reported to be accompanied by a DMD phenotype [75] and to produce no dystrophin (personal communication). On contrast, there are no patients reported for the deletion of exons [44][45], signifying that the deletion may be asymptomatic.…”