The Dystrophin Complex: Structure, Function, and Implications for Therapy

Abstract

The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, triggers instability of the plasma membrane and myofiber loss. Mutations in dystrophin have been extensively cataloged providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.

Dystrophin is expressed in smooth muscle and afferent nerve fibers in the rat urinary bladder

“…The DMD gene produces a range of different transcripts encoding various dystrophin isoforms ranging in size with molecular weights of 71, 116, 140, 260, and 427 kDa. The main isoform found in striated muscle tissue is known as the full‐length isoform , Dp427m . Shorter isoforms Dp71 and Dp140 are particularly of interest in relation to micturition pathophysiology because of their expression in smooth muscle tissue as well as in the nervous system .…”

“…Morphological changes could be accompanied by alterations in dystrophin expression . In addition, changes occurring in the cellular localization of other DGC proteins in DMD are a secondary consequence of the absence of dystrophin . Having considered these morphological changes and the occurrence of age‐related LUTS in DMD, we sought to evaluate dystrophin isoform expression during postnatal development of the healthy rat urinary bladder.…”

The sodium channel NaX: Possible player in excitation–contraction coupling

“…Numerous examples exist showing expressional dependence among proteins that function together and/or are part of the same signaling pathway. To illustrate one example, in skeletal muscle, the dystrophin glycoprotein complex (DGC) stabilizes the plasma membrane by anchoring the cytoskeleton to the extracellular matrix . The DGC is composed of dystrophin, the sarcoglycans (α, β, γ, δ) and numerous other proteins .…”

“…To illustrate one example, in skeletal muscle, the dystrophin glycoprotein complex (DGC) stabilizes the plasma membrane by anchoring the cytoskeleton to the extracellular matrix . The DGC is composed of dystrophin, the sarcoglycans (α, β, γ, δ) and numerous other proteins . Mice lacking dystrophin show marked reductions in all sarcoglycans while in mice lacking γ‐sarcoglycan, the expression of β‐sarcoglycan and δ‐sarcoglycan are reduced .…”

Gene Editing for the Heart

“…Dystrophin binds actin at its N-terminus and with its C-terminus, dystrophin connects to the plasma membrane of myocytes. The central portion of dystrophin is composed of multiple spectrin repeat domains, and mutations that interrupt the internal spectrin repeat domains and leave intact the N- and C-terminus result in a milder form of disease called Becker Muscular Dystrophy 1 . A major therapeutic approach for DMD aims to restore the reading frame by converting DMD-associated frame-disrupting mutations into those that produce internally deleted but more functional BMD-associated dystrophins.…”