Unlocking the heart’s genetic secrets

By Laura Eggertson

Whenever she hears about the sudden death of a young athlete who has collapsed with heart failure on a hockey rink, soccer field or basketball court, Mona Nemer is painfully reminded of the importance of her work.

Nemer, uOttawa’s Vice-President, Research, is a biochemist and molecular cardiologist. Her pioneering work involves discovering genes critical for normal heart development – genes that, if mutated or absent, lead to birth defects or heart disease.

One of those genes, which Nemer and her team identified, is GATA4. The nondescript name does not do justice to the gene’s vital function: if defective, GATA4 can cause a condition called atrial septal defect, a tiny hole between the two chambers of the heart.

This hole is so small it may remain undetected. But an atrial septal defect can disrupt the heart’s blood flow, oxygenation and pressure. It is often the cause of the sudden, and sometimes fatal, collapse of otherwise healthy young athletes who no one knew had the problem.

“Every year, we hear about a player who collapses during a game and, inevitably, they later diagnose a congenital heart defect,” says Nemer, who is also a professor at uOttawa’s Faculty of Medicine.

Ultimate goal: preventing disease

Identifying the gene responsible is the first step in diagnosing and, one day, preventing the cardiac disease that people born with these defects may experience. And identification alone isn’t enough, Nemer points out, because not everyone with the genetic mutation will have the same structural heart defect. Additional genetic and environmental factors can change the outcome, even for siblings, she says.

“The new frontier is to understand what the modifiers are that will actually cause the same change (in a gene) to be linked to a defect in one person, but not to cause any defect in another person,” she says.

Although Nemer’s research involves studying the biochemistry of animal models, she collaborates with researchers at the University of Ottawa Heart Institute and networks in Montreal, England and Australia to investigate how her findings translate into human genomics.

“The ultimate goal is to prevent these birth defects, and I think we will likely be able to prevent some, but not all of them,” Nemer says.

In the meantime, knowing that someone carries a mutated copy of the gene, and thus faces a higher risk of cardiac disease, could lead to better screening and follow-up, as well as lifestyle interventions aimed at prevention.

Second gene identified 

In addition to GATA4, Nemer and her colleagues have also identified GATA5, another cardiac gene they have linked to two critical issues: blood pressure regulation and bicuspid aortic valve defect. This is another common heart defect that results in babies being born with two rather than three leaflets (branches) on the aortic valve.

The uOttawa researchers now know that GATA5 interferes with blood pressure regulation by causing defects in small blood vessels. Those defects increase blood pressure and can eventually lead to heart attacks. The gene also interferes with the normal functioning of heart valves and can disrupt the heart’s normal rhythm. It is the main reason why some people under 60 require valve replacements.

The heart was not Nemer’s initial research interest. During her post-doctoral studies, she was investigating the brain – until colleagues who had discovered a new cardiac hormone asked her to help them clone the gene. She did, and was seduced by the mysteries of the often-romanticized organ.

“I was absolutely fascinated. It’s such a vital organ and so little was known about its function,” Nemer says. “People assumed it was a pump – a very simplistic view of the heart.”

Once she realized that cardiac cells, unlike the cells of other organs, do not regenerate, and that cardiovascular disease remains one of the major chronic diseases and causes of death, she was hooked. She changed her area of study.

Advancing regenerative medicine

Today, Nemer hopes her research to identify the genes and proteins that drive the normal formation of the heart will also advance regenerative medicine. In the next decade, she believes that researchers will be able to grow cardiac cells outside the body that will, once they are grafted onto the heart, help repair damaged tissue.

Although researchers have begun that process, they haven’t yet captured all the “ingredients” – the different genes – that could help repair specific areas of the heart, such as valves. Nemer’s discovery of the important roles played by GATA4 and GATA5 may lead to the development of more targeted, regenerative heart cells.

“This is the kind of incremental knowledge that we are collecting. Once you have a key, you can unlock other things,” explains Nemer, whose term as the University’s Vice-President, Research, was recently extended to June 30, 2017. "We are extremely well placed to continue making discoveries, but just as importantly, to translate them into better patient care.”

Main photo:
Mona Nemer works in the lab alongside PhD candidate Jamie Whitcomb. Photo: Bonnie Findley