The mutation alters a protein involved in regulating the flow of calcium in and out of the muscle cells. That flow causes the heart to contract and expand regularly, pumping blood to the body.
The mutation was first discovered in mice. Now researchers at the University of Toronto and Harvard Medical School say they have found it in a family with a history of a particularly deadly inherited form of heart failure that can be fatal in the 20s or 30s, says a report in the Feb. 28 issue of Science.
Calcium flow is a key element in heart function. For the heart to contract, calcium must be released into the main body of heart cells; the more calcium that flows in, the stronger the force of contraction. When the heart relaxes, calcium is pumped out of the cells. The newly described mutation alters a protein called phospholamban, which helps regulates this calcium pump.
Calcium channel blocker drugs are sometimes used to treat heart failure. They reduce the flow of calcium into the heart muscles, easing the strain on the heart. A new class of drugs based on control of phospholamban function could provide another way to reduce the ill effects of heart failure, in which the heart gradually loses its pumping ability, says study author Dr. David MacLennan, a professor of medical research at the University of Toronto.
"Phospholamban has been considered to be target for some time, and a lot of companies have tried to develop medications that control it," MacLennan says.
Until now, work on phospholamban has centered entirely on mice. The journal report is important because it is "the first case where a mutation of phospholamban has been shown to be a causal gene for human dilated cardiomyopathy," in which abnormal enlargement reduces the heart's pumping ability, MacLennan says.
"It is a powerful target because it has specific action in the heart," while calcium channel blockers affect the entire body, says Dr. Christine E. Seidman, director of cardiovascular genetics at Harvard Medical School and a member of the research team.
The mutation itself is rare. It was found in just one of 20 individuals with dilated cardiomyopathy. A study of that person's family showed a history of that kind of heart failure, with affected members developing heart failure in their 20s and usually dying within 10 years. Seidman's laboratory sequenced the gene, finding that a change in just one of the chain of amino acids making up the protein caused the problem.
"The importance of this is not this particular mutation in this particular family," Seidman says. "The importance is to implicate that it is an altered balance of calcium that causes heart failure. Knowing that calcium disregulation is important implies that addressing it might have therapeutic applications."
Heart failure is a leading cause of death in the United States and Canada. More than 2 million Americans have heart failure, and it causes 40,000 deaths in the United States each year.