Mechanisms of TTN tv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

Abstract

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies.

Keywords: dilated cardiomyopathy; titin; zebrafish.

Figure 1

Schematic of sarcomere structure. Sarcomeres are the functional units of cardiomyocytes. Each sarcomere contains rows of interdigitating thin (pink) and thick (yellow) filaments comprised of actin and myosin, respectively. Each titin protein (cyan) spans half-sarcomeres from the Z-disc to the M-line.

Figure 2

Schematic of the human TTN gene (meta-transcript) and the two zebrafish titin genes, ttna and ttnb. Titin contains four sub-domains (Z-line, I-band, A-band, M-line) that are conserved between humans and zebrafish. The locations of mutations in the zebrafish ttna and ttnb genes are indicated by arrows and labelled according to published mutant allele names (see Table 1 for more details). Phenotype data are available for embryonic mutants in all lines; yellow stars denote mutant lines in which cardiac function has also been evaluated in adult fish. Additional double mutant lines have also been generated by Shih et al. (2016) including xu068, xu069, xu070 and xu071, each of which possesses different combinations of the xu064, xu065, xu066 and xu067 alleles indicated in this figure (see Table 1 for more details).