Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• Duchenne and Becker Muscular Dystrophies (DMD/BMD) are genetic disorders caused by mutations in the dystrophin gene.
• Standard mutation detection often focuses on exons and flanking regions, potentially missing intronic mutations.

Observation:

• Four unrelated DMD/BMD patients without gross gene defects exhibited unexpected out-of-frame sequences in muscle dystrophin mRNA.
• These sequences originated from cryptic exons within large introns, activated by intronic point mutations.

Findings:

• In silico analysis identified cryptic exons with specific splice site characteristics in introns 60, 9, 1M, and 62.
• Intronic point mutations were found to activate these cryptic donor or acceptor splice sites, leading to altered mRNA splicing.
• Patients presented with a Becker Muscular Dystrophy/intermediate phenotype, with reduced normally spliced transcripts but normal dystrophin levels.

Implications:

• This study reveals a novel class of intronic mutations in the dystrophin gene, accounting for 6% of small mutations in the series.
• Current diagnostic approaches focusing solely on exons may overlook these cryptic exon-mediated mutations.
• Comprehensive genetic analysis including intronic regions is crucial for accurate DMD/BMD diagnosis.