Genetic Studies of Sarcomere-based Cardiac Diseases

Sarcomere-based Cardiac Diseases Genetic Studies

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 studies 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, are the most common genetic factors 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 is derived from the characterization of pickwick, a group of zebrafish mutants 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 identified a nonsense mutation in a cardiac-specific exon of titin. Genome editing technology enabled a panel of TTNtvs in zebrafish to be generated. These mutants are investigated to elucidate mechanisms underlying allelic heterogeneity, to seek genetic modifiers and to develop effective therapies for TTNtv-based DCM.