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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 microdystrophin ΔR4-R23/ΔCT  with a large deletion in the hinge 3 region. Inclusion of polyproline in microdystrophin ΔR4-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 microdystrophin ΔR4-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 α-helical structure of the polyproline site significantly impairs the functional capacity of truncated dystrophins to maintain appropriate connections between the cytoskeleton and extracellular matrix.

The Polyproline Site in Hinge 2 Influences the Functional Capacity of Truncated Dystrophins