Low-level dystrophin expression attenuating the dystrophinopathy phenotype

Area of Science:

• Genetics
• Molecular Biology
• Neuromuscular Disorders

Background:

• The reading frame rule posits Duchenne muscular dystrophy (DMD) arises from out-of-frame transcripts and Becker muscular dystrophy from in-frame transcripts.
• Nonsense mutations, typically causing truncated proteins, can sometimes lead to altered splicing and in-frame transcripts.

Observation:

• A 10-year-old boy with a predicted exon 42 nonsense mutation presented with intermediate muscular dystrophy, walking 157% further than DMD controls.
• Muscle biopsy revealed a low percentage (6.0-9.8%) of in-frame DMD transcripts and minimal dystrophin protein expression (3.2%).

Findings:

• Despite a predicted nonsense mutation, a significant portion of DMD transcripts were in-frame, excluding exon 42.
• Low levels of dystrophin protein expression were observed, contradicting typical DMD severity.
• Homozygosity for the IAAM LTBP4 haplotype was identified as a potential genetic modifier.

Implications:

• This case challenges the strict reading frame rule in DMD pathogenesis.
• Very low dystrophin expression may ameliorate skeletal muscle weakness, suggesting a therapeutic threshold.
• Findings are relevant for developing and evaluating dystrophin-restoring therapies for DMD.