2.1.2. Cytoskeleton

Mutations in genes encoding cytoskeletal proteins in cardiac muscle are also highly associated with DCM. The loss of dystrophin results in DCM [41], including X-linked DCM where heart dysfunction and failure can be highly pronounced [27]. Mutations in proteins that interact with dystrophin, such as the sarcoglycans, can also represent causal genetic loci for DCM [42]. Although these proteins are found in both skeletal and cardiac muscle, mutations in some of these proteins can cause heart disease without significant skeletal muscle deficits [43]. Other commonly targeted proteins include desmin, vinculin, and z-band alternatively spliced PDZ-motif (ZASP) [44,45]. These proteins are integral for maintaining the connection between muscle fibers, the sarcolemma, and the extracelluar matrix. Mutations in cytoskeletal proteins generally inhibit myocyte force transmission and increase muscle membrane instability and permeability. The compromised sarcolemma leaves the muscle cell susceptible to increases in intracellular calcium, which can result in calcium overload and myocyte death [41,46].
