Discovery in SF could unlock origins of heart defects


More than a million people in the U.S. suffer from congenital heart disease, but now researchers at San Francisco's Gladstone Institutes believe a kind of genetic switch, flipped in the wrong position before birth, could be responsible for at least some of those cases.

"Normally, when we think about heart development or the formation of any organ, we usually think about what genes do we need to turn on so that tissue becomes what it's supposed to be," Dr. Benoit Bruneau explains. Instead, he and his team decided to do the opposite. Using a mouse model, they turned off a master gene that regulates the development of cells into cardiac myocytes, which ultimately form the tissue of the heart. He says they expected those cells to lose the ability to develop. "It was a real shocker when we saw these mice walking around with structurally normal hearts," Bruneau says.

In fact, the animals developed normally in the uterus and showed no outward signs of heart problems at birth. However, the Gladstone teams believes that what happened next could hold clues to the formation of heart defects in humans and potentially lead to a new way to treat them. Bruneau's team kept monitoring the animals and while they were born normally, he says they began to develop a deadly defect as they continued to grow. "We ended up with mice that were born, but then their hearts became massive. They had massing enlarged hearts," Bruneau says.

He believes the enlarged hearts were likely caused by a second gene that was meant to be turned on or off after birth by the gene regulator they had removed. If researchers were able to find markers for similar malfunctioning genes in humans, there is the potential of treating heart defects in the womb. "They're only discovered once they've already happened. If we could find earlier markers and earlier intervention to prevent them in the first place, that would be the ideal scenario," Bruneau says.

Bruneau says the team's next goal is to find out how other genes in the heart are regulated. He says the information could ultimately lead to a genomic blueprint of how a heart becomes a heart.

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