The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins

Mutations in dystrophin can lead to duchenne muscular dystrophy or the more mild form of the disease,becker muscular dystrophy. the hinge 3 region in the rod domain of dystrophin is particularly prone to deletion mutations. in-frame deletions of hinge 3 are predicted to lead to bmd,however the severity of disease can vary considerably. here we performed extensive structure-function analyses of truncated dystrophins with modified hinges and spectrin-like repeats in mdx mice. we found that the polyproline site in hinge 2 profoundly influences the functional capacity of a microdystrophinδr4-r23/δ;ct with a large deletion in the hinge 3 region. inclusion of polyproline in microdystrophinδr4-r23/δct led to small myofibers (12% smaller than wild-type),achilles myotendinous disruption,ringed fibers,and aberrant neuromuscular junctions in the mdx gastrocnemius muscles. replacing hinge 2 of microdystrophinδr4-r23/δct with hinge 3 significantly improved the functional capacity to prevent muscle degeneration,increase muscle fiber area,and maintain the junctions. we conclude that the rigid a-helical structure of the polyproline site significantly impairs the functional capacity of truncated dystrophins to maintain appropriate connections between the cytoskeleton and extracellular matrix. © 2010 banks et al.