Genetic underpinnings of congenital heart disease

Genetic underpinnings of congenital heart disease

Approximately 1.4 million children and adults in the United States are currently living with a congenital heart defect.  One of the most common defects is a hole in the septum - the wall that divides the right side of the heart from the left. As a result, blood flows to the wrong place or in the wrong direction, and the body's tissues stop receiving the oxygen they need to function properly.

Mutations in the TBX5 gene cause the rare Holt-Oram syndrome and the more prevalent Tetralogy of Fallot, two conditions marked by septal defects. Over the last two decades, mounting evidence has indicated that this gene acts as a transcription factor, a kind of master switch that turns on other genes during development. But no one had been able to figure out which genes TBX5 controls in the developing heart, and how.

 team led by researchers at the University of North Carolina at Chapel Hill has now found evidence pointing to a culprit. The scientists discovered that the TBX5 mutations allow other genes normally involved in cancer and the nervous system to be inappropriately "turned on" or expressed in the developing heart. This gene expression could play a major role in congenital heart disease.

First, the researchers stuck a tag on the TBX5 protein so they could extract it from heart tissue along with all its other associated proteins. They pulled down approximately 100 proteins, including some members of the "NuRD repressor complex" that is known for tightly winding up sections of DNA in a way that turns off a variety of different genes.

Using molecular modeling and traditional genetic cross breeding in mice, the researchers showed that TBX5 binds to DNA and recruits this NuRD complex, which then represses genes normally activated in cancer and in the nervous system.

Finally, the group engineered tissue culture cells to carry the same mutations that cause heart disease in patients and showed that the mutations disrupted the interaction between TBX5 and NuRD, leading to the inappropriate activation of cancer and neural genes in the heart.

"We believe that these cancer genes could fuel the incorrect growth of the heart, and the neural genes could trigger cardiac conduction abnormalities, both of which are commonly found in congenital heart disease," said the author.

The finding, published in the journal Developmental Cell, provides insight into how patients develop heart disease and a road map for future studies on other genetic defects that lead to a malfunctioning heart.