Mar. 24, 2005 There are a few people in the world who get heart disease after they begin to lose their hearing. Harvard Medical School researchers have found a gene responsible for this, and they're using that information to better understand heart problems faced by millions of people.
Two members of a family who suffered progressive hearing loss and then underwent heart transplants got Christine Seidman, a professor of medicine, interested in the strange connection. Their hearing loss began early in life. It progressed for at least 10 years before they started to experience shortness of breath, chest pains, and other symptoms of congestive heart failure. This condition, in which heart muscles become too weak to pump enough blood to the lungs and heart, kills about 260,000 people a year. However, the heart transplants received by these two people were successful and they are now living healthy lives.
Taking the novel connection to heart, Seidman and her colleagues set out to find the cause. Their studies of family members with the syndrome revealed that they shared a mutation in a gene called eya4.
To look more closely at how changes in the protein made by this gene work, the researchers turned to the tiny zebrafish. Half the length of a finger, these fish possess an eya4 gene remarkably similar to that of humans. What's more, zebrafish have almost transparent bodies. You can see and even take pictures of their hearts and watch the blood it pumps go from place to place.
The fish are easy to maintain and manipulate, and they can serve as a good model of the heart failure that affects millions of people and is becoming epidemic in this country.
Breaking the hearts of fish
The fish received injections of genetic blockers that prevented their eya4 gene from producing a key protein that turns on other genes necessary for normal heart function. When the team took photographs of these modified fish, "We saw dramatic changes in the size of their chest cavities due to increased fluid surrounding the heart," Seidman recalls. "A closer look showed the organ was contracting, or beating, abnormally."
As a final check, the team tracked the movement of blood along the body to the tail. They saw a profound decrease in blood flow in the doctored fish compared to that in wild fish.
"The importance of this discovery goes beyond finding the cause of an unusual human mutation," Seidman notes. Many genes that cause heart failure have been found by her team and other investigators, but they code for individual tasks such as making a heart beat or building an ear bone. In contrast, eya4 takes part in regulation of a large repertoire of genes needed for normal heart function. Thus, "studying eya4 gives us a new tool to overview the whole of heart function," Seidman says. "That's the real excitement of this work."
Much of the work was done by Jost Schonberger and Libin Wang, two postdoctoral fellows on the team. Jonathan Seidman, a professor of genetics at Harvard Medical School and Christine's husband, also participated in the research, which is described in detail in the April issue of Nature Genetics.
Do fish go deaf?
In people with the eya4 mutation, hearing loss starts decades before the symptoms of a failing heart appear. "We could therefore use the hearing loss as a [predictor] for heart disease," Seidman notes.
"But we are also very interested in the role of eya4 in hearing," she continues. She wants to explore the heart of hearing, so to speak. While the researchers can use zebrafish to investigate some aspects of this, it's technically easier to probe hearing by using mice as models. Scientists don't know much about how fish hear, or if they go deaf.
The mouse work has already begun. Seidman is intrigued to learn why a gene that has survived hundreds of millions of years of evolution from fish to humans got involved in both hearing and heartbeats. "The heart and ear don't seem to have much in common," she says. "But, if an efficient way to regulate gene expression evolves in an organ such as the ear, evolution might well want to conserve it and use it for other purposes in other tissues. A fuller understanding of what happens when a critical regulator like eya4 doesn't function normally can lead us to novel and creative ways to redress medical problems that involve both the heart and hearing."
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