Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy

Circ Cardiovasc Genet. 2009 Dec;2(6):544-51. doi: 10.1161/CIRCGENETICS.109.867242. Epub 2009 Sep 30.


Background: Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy often result from deletion mutations in the dystrophin gene that may lead to expression of an altered dystrophin protein in cardiac muscle. Cardiac involvement is present in approximately 70% of BMD and all X-linked dilated cardiomyopathy cases. To date, the timing of cardiomyopathy development remains unpredictable. We analyzed 78 BMD and X-linked dilated cardiomyopathy patients with common deletion mutations predicted to alter the dystrophin protein and correlated their mutations to cardiomyopathy age of onset. This approach was chosen to connect dystrophin structure with function in the heart.

Methods and results: Detailed cardiac information was collected for BMD and X-linked dilated cardiomyopathy patients with defined dystrophin gene deletion mutations. Patients were grouped based on the dystrophin protein domain affected by the deletion. Deletions affecting the amino-terminal domain are associated with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions removing part of the rod domain and hinge 3 have a later-onset DCM (mid-40s). Further, we modeled the effects of the most common mutations occurring in the rod domain on the overall structure of the dystrophin protein. By combining genetic and protein information, this analysis revealed a strong correlation between specific protein structural modifications and DCM age of onset.

Conclusions: We identified specific regions of the dystrophin gene that when mutated predispose BMD patients to early-onset DCM. In addition, we propose that some mutations lead to early-onset DCM by specific alterations in protein folding. These findings have potential implications for early intervention in the cardiac care of BMD patients and for therapeutic approaches that target the heart in dystrophinopathies.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Cardiomyopathy, Dilated / genetics*
  • Child
  • Cross-Sectional Studies
  • Dystrophin / genetics*
  • Female
  • Humans
  • Male
  • Muscular Dystrophy, Duchenne / epidemiology*
  • Muscular Dystrophy, Duchenne / genetics*
  • Sequence Deletion*
  • Young Adult


  • Dystrophin