The defect has been identified in a French family in which sudden death is common, says a report in the Feb. 6 issue of Nature. However, it could be involved not only in sudden cardiac deaths but also in many other diseases, says study author Peter Mohler, a Howard Hughes Medical Institute postdoctoral fellow at Duke University Medical Center.
The defect is a mutation of a gene that codes for a protein called ankyrin-B, which plays an important -- but until now unknown -- role in the complex series of electrical and chemical events that govern the heartbeat. A beat starts with a moment of rest, the QT interval, so called because of its designation on an electrocardiogram. That interval ends as microscopic pores, or channels, in the heart muscle are created, allowing ions -- charged particles -- of chemicals such as calcium, potassium, sodium and chloride to flow through these ion channels, carrying the electric signals that make the heart contract and expand.
Many arrhythmias, life-threatening abnormal heartbeats, have been related to malfunctions of the ion channels. Ankyrin-B is unique, Mohler says, because its role is to put those channels in the proper locations. "It takes them where they need to be at the cell membrane, so they don't float away," he says. "This protein gets them there and keeps them there."
The QT interval normally lasts about four-tenths of a second. A lack of ankyrin-B prolongs that interval to half a second -- just long enough to increase the possibility of a fatal arrhythmia. In the "fairly small population of French people," the mutation has led to a family history of sudden death, Mohler says.
"They have been dying sudden deaths for centuries, as early as the age of 19," he says. "One of them died while running up a hill. Another died while being awakened suddenly."
Using a specially bred stain of mice, the Duke researchers are exploring the implications of their discovery. "We hope to understand more about the cellular pathway that this protein uses for targeting the ion channels of the heart," says Dr. Vann Bennett, professor of cell biology at Duke and leader of the research team.
There is a prospect of using the discovery to improve heart treatment, he says. "It has not escaped our notice that one consequence of the mutation is to lower intracellular levels of calcium," Bennett says. "This can be very bad. If we could raise calcium levels in a controlled way, the heart could actually be stronger, so this would be a way of helping heart failure."
The researchers are also looking into its possible role in other diseases. "Ankyrin is found in many tissues and organs, and very little is known about it," Bennett says. It appears to have an important role in the pancreas, where insulin is produced, and mice with the genetic abnormality develop a mild form of diabetes, Mohler says.
The experiments could have implications for disorders of other organs that have excitable membranes like those in the heart, he says. These include the nervous system and the linings of the lungs and kidneys.