Scientists studying one family’s genetics to better understand congenital heart disease have discovered more than they bargained for. They found that a mutation that causes babies to be born with a hole in the heart also causes heart failure in adolescence. The findings have uncovered a potential new target for heart disease.
In 2013, Gladstone Institutes scientists sequenced the family’s genes because half of their children had been born with a hole in their septum, the wall separating the heart’s chambers. The team pinpointed a mutation in the gene Gata4, which codes for a protein of the same name, as the cause of the birth defects, according to a statement.
Fast forward 7 years: multiple family members developed a different heart condition in adolescence that made the heart pump abnormally. To solve the mystery, the researchers used stem cell technology to reprogram the family’s skin cells into heart cells.
They found that in addition to beating weakly, these heart cells had many genes, such as the genes that dictate septum development, that were abnormally switched on or off, according to the statement. And that’s not all--some genes that affect the development of other organs were silenced too.
“By studying the patients’ heart cells in a dish, we were able to figure out why their hearts were not pumping properly,” said Dr. Deepak Srivastava, director of the Gladstone Institutes and a senior author on the study. “Investigating their genetic mutation revealed a whole network of genes that went awry, first causing septal defects and then the heart muscle dysfunction.”
The researchers discovered that the Gata4 mutation didn’t just affect production of the Gata4 protein--it also blocked the recruitment of another protein, Tbx5, to genes that play a role in heart development and muscle contraction. Essentially, the Gata4 mutation has a domino effect: it disrupts “virtually the entire network of genes” that are regulated by Gata4 and Tbx5.
Gata4 and Tbx5 have long been of interest to Gladstone's researchers. In November, they reported that they used normal versions of the proteins, along with one other, to transform scarred heart muscle back into healthy tissue.
Because the effect of “master regulator” proteins, such as Gata4 and Tbx5, are so wide-ranging, they are difficult to target with drugs. But the researchers identified a “hub” of genes affected by Gata4 that could be a potential therapeutic target. The team is investigating an existing drug that targets this pathway as a potential treatment for heart disease.