Zebrafish Genetics: Xiaolei Xu

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 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. These genetic factors account for 25% of dilated cardiomyopathy cases.

This research direction is derived from the characterization of pickwick, a group of mutated zebrafish identified during a large-scale mutagenesis screen. The hearts in pickwick embryos manifest weak cardiac contractility, thin and stretched myocardial cell morphology, and significantly reduced ventricular pressure — like people with dilated cardiomyopathy.

Through 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. This panel is being investigated to seek genetic modifiers to decipher pathological events and develop effective therapies for TTNtv-based dilated cardiomyopathy.