Mutant ZASP in Cytoskeletal Remodeling and Arrhythmia

Baylor College Of Medicine, Houston TX

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Abstract

DESCRIPTION (provided by applicant): Dilated cardiomyopathy (DCM) is a major cause of heart failure and is often associated with various forms of muscular dystrophies, including Duchenne, Becker and Limb Girdle Muscular Dystrophy (LGMD). In addition to the hemodynamic impairment, secondary arrhythmias occur hampering an already fragile clinical scenario. Mutations in sarcolemmal components such as dystrophin and the dystrophin glycoprotein complex (DGC) cause extensive fiber damage in skeletal and cardiac muscle of patients and animal models with muscular dystrophy and cardiomyopathy suggesting that sarcolemmal integrity is key in both cytoskeletal remodeling and arrhythmias. In striated muscles, sarcolemmal invaginations form the transverse tubule (T-tubule), which provide spatial and temporal coupling between membrane excitation and the contractile function though the sarcomeric Z-line. Recently, we identified mutations in the Z-band alternatively spliced PDZ-motif protein (ZASP), a novel component of the Z-line in cardiac and skeletal muscle causing DCM or left ventricular non-compaction (LVNC), a defect of left ventricular morphogenesis. ZASP, the human homolog of the murine Cypher gene, encodes multiple isoforms with uncharacterized expression patterns. In addition, little is known about the role of Cypher/ZASP mutations in skeletal muscle, and we have suggested that Cypher/ZASP could be a candidate for orphan forms of muscular dystrophies.