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 hypertrophic cardiomyopathy. We are performing genetic studies in zebrafish to dissect the molecular mechanisms of sarcomere assembly, and to understand the pathological consequences resulting from misassembly. Currently we are focusing upon titin, which encodes a giant protein that may behave as the template for sarcomere assembly. We are also interested in other sarcomeric genes such as myosin light chains and telethonin.

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 later found in human patients with dilated cardiomyopathy.