Published Online
on September 30, 2009

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Original Article

Analysis of Dystrophin Deletion Mutations Predicts Age of Cardiomyopathy Onset in Becker Muscular Dystrophy

Rita WenKaspar¹; Hugh D. Allen¹; Will C. Ray¹; Carlos E. Alvarez¹; John T. Kissel²; Alan Pestronk³; Robert B. Weiss⁴; Kevin M. Flanigan⁴; Jerry R. Mendell¹ and Federica Montanaro^1,5

¹ Nationwide Children's Hospital & The Ohio State Univ, Columbus, OH;
² The Ohio State University, Columbus, OH;
³ Washington University, St. Louis, MO;
⁴ University of Utah, Salt Lake City, UT

^* Corresponding author; email: montanaf{at}pediatrics.ohio-state.edu

Background—Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy (XLDCM) 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 about 70% of BMD and all XLDCM cases. To date, the timing of cardiomyopathy development remains unpredictable. We analyzed 78 BMD and XLDCM 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 XLDCM 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 DCM (mid-20's), while deletions removing part of the rod domain and hinge 3 have a later onset DCM (mid-40's). 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 via 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.

Key Words: cardiomyopathy • genetics • risk factors • Dystrophin • Muscular dystrophies