Abstract
DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements.
Highlights
Dystrophinopathies are the most frequent neuromuscular disorder
We describe a comprehensive analysis of 98 Duchenne muscular dystrophy (DMD) point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression
Bioinformatics analysis of nonsense/ frameshift mutations revealed that putative splicing enhancers (PESE)/PESS matrix is a powerful tool to predict critical regulatory regions for BMDassociated exon-skipping
Summary
Dystrophinopathies are the most frequent neuromuscular disorder. They are caused by mutations in the DMD gene, one of the largest genes found in humans [1,2]. DMD encodes for dystrophin, a key player in the stabilization of the sarcolemma during muscle contraction [3]. Clinical phenotypes include severe Duchenne muscular dystrophy (DMD), milder Becker muscular dystrophy (BMD), intermediate muscular dystrophy (IMD) and pure cardiac X-linked dilated cardiomyopathy (XLCM). DMD is characterized by early-onset, rapidly progressive muscular weakness, leading to wheel-chair dependency before age 13 and death during the third decade. BMD is clinically heterogeneous but presents a later onset and slower progression [4]
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