Genetic Studies of Sarcomere-based Cardiac Diseases

The sarcomere is the basic contractile unit for striated muscles such as cardiomyocytes. Mutations in sarcomeric genes have been linked to many human diseases, including cardiomyopathy and muscular dystrophy. We are performing genetic studies in zebrafish to dissect the molecular mechanisms of sarcomere assembly, and to understand the pathological consequences resulting from misassembly.

We have been studying titin, which encodes a giant protein that may behave as the template for sarcomere assembly. This research direction was derived from the characterization of pickwick, a group of zebrafish mutants that were identified during a large-scale mutagenesis screen. The hearts in pik embryos manifest weak cardiac contractility, thin and stretched myocardial cell morphology, and significantly reduced ventricular pressure, which resemble those in human dilated cardiomyopathy. By positional cloning means, we identified a mutation in a cardiac-specific exon of titin. Interestingly, similar mutations were found in human patients with dilated cardiomyopathy

We showed that zebrafish is an excellent in vivo animal model for studying myofibrillogenesis. At least five mid-steps of sarcomere assembly have been uncovered in a developing zebrafish heart. We also demonstrated that it is feasible to conduct systematic genetic studies of saromeric genes using zebrafish model. Currently, we are focusing upon genes encoding proteins in the Z-disc, a sarcomeric sub-structure that has been implicated as a stretch sensor and a signaling center during pathogenesis of cardiac hypertrophy.