Biologists explain mechanisms behind CHD4-related heart defects

Mutations in the CHD4 gene are known contributors to congenital heart defects. Biologists at the University of North Carolina School of Medicine believe they are beginning to understand why.

In their mouse study published June 11 in Proceedings of the National Academy of Sciences, the researchers found repression of the CHD4 protein causes cardiomyocytes to take on muscle-filament proteins meant for non-heart muscle cells. This facilitates the development of “hybrid” heart cells that don’t pump blood as effectively as normal heart cells.

“For patients with congenital heart defects linked to CHD4 mutations, this research helps explain why their hearts don’t work as well as normal, and suggests strategies for therapeutic intervention,” senior study author Frank Conlon, PhD, a professor of biology and genetics at UNC, said in a press release.

The researchers arrived at these conclusions after removing the CHD4 gene from the heart cells of mice embryos. None of the mice were born alive due to severe cardiac defects developed during gestation, and all of them showed ultrasound evidence of reduced ventricular function.

"At this stage of cardiac development in mouse, continued embryonic growth is dependent on the formation of functional cardiac sarcomere units to initiate systolic function,” Conlon and colleagues wrote. “Our data support a model in which CHD4 loss impedes this process during early heart development. This poses an intriguing question whether in humans, impaired cardiac systolic function associated with certain cardiomyopathies or cardiac failure, in the absence of mutations in cardiac sarcomere subunits, may be due to improper expression and intercalation of noncardiac myofibril paralogs in the cardiac sarcomere.”

The researchers next plan to investigate specific CHD4 mutations and their impact on human cardiac defects, according to the release. They said novel therapies to restore the appropriate repression of non-cardiac myofiber proteins could prevent congenital defects when CHD4 mutations are detected.