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. The Zebrafish Genetics Laboratory has been studying titin (TTN), which encodes the largest protein that functions as the template for sarcomere assembly. TTN truncating variants (TTNtvs), including nonsense, frameshift and essential splice site mutations, have been recently found to be the most common genetic factor for dilated cardiomyopathy (DCM), accounting for 25 percent of DCM cases. However, the presence of a TTNtv is not equal to DCM because TTNtvs are also found in reference populations. It remains elusive why pathogenic TTNtvs are mainly found in the C-terminal A-band region of TTN (TTNtv-A's) but less enriched in the N-terminal Z-disk region (TTNtv-Z's).

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 pick embryos manifest weak cardiac contractility, thin and stretched myocardial cell morphology, and significantly reduced ventricular pressure, like people with dilated cardiomyopathy. By means of positional cloning, The Zebrafish Genetics Lab team has identified a nonsense mutation in a cardiac-specific exon of titin. Taking advantage of the genome editing technology, a panel of TTNtvs in zebrafish has been generated. These mutants are being investigated to elucidate mechanisms underlying allelic heterogeneity, to seek genetic modifiers and to develop effective therapies for TTNtv-based DCM.