Low-level dystrophin expression attenuating the dystrophinopathy phenotype

Neuromuscul Disord. 2018 Feb;28(2):116-121. doi: 10.1016/j.nmd.2017.11.007. Epub 2017 Nov 23.


The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and an in-frame transcript. Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy. RNA sequencing analysis from a muscle biopsy revealed only 6.0-9.8% of DMD transcripts were in-frame, excluding exon 42, and immunoblot demonstrated only 3.2% dystrophin protein expression. Another potential genetic modifier noted was homozygosity for the protective IAAM LTBP4 haplotype. This case suggests that very low levels of DMD exon skipping and dystrophin protein expression may result in amelioration of skeletal muscle weakness, a finding relevant to current dystrophin-restoring therapies.

Keywords: Dystrophin; Intermediate muscular dystrophy; Nonsense mutation; RNA sequencing.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Codon, Nonsense*
  • Dystrophin / genetics*
  • Dystrophin / metabolism*
  • Exons
  • Gene Expression
  • Humans
  • Male
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / metabolism*
  • Muscular Dystrophy, Duchenne / pathology
  • Phenotype


  • Codon, Nonsense
  • DMD protein, human
  • Dystrophin