Seizing two genes for fast heartbeat.

Researchers say they have fingered two genes underlying a lethal heart rhythm abnormality that can strike young, healthy people without warning. The finding, reported this week, may pave the way for early diagnosis and treatment of individuals who have inherited this condition, which occurs in about 1 in 10,000 individuals. More than 300,000 people in the United States die suddenly each year; in many cases the underlying cause may be an aberrant cardiac rhythm.

The disorder is called long QT syndrome for the abnormally long wave it may produce on an electrocardiogram, a tracing of the electrical activity of the heart. The first indication of trouble may surface suddenly, in the form of an episode of rapid, irregular heartbeat. That ineffective heart rhythm can lead to blackout spells and even death.

Mark T. Keating of the Howard Hughes Medical Institute at the University of Utah Health Sciences Center in Salt Lake City and his colleagues had previously reported that certain regions of chromosomes 7, 3, and 11 appear to contain genes responsible for this deadly syndrome.

They also knew of the discovery by another research team of a gene on chromosome 7 believed to contain the blueprint for an ion channel, a protein embedded in the surface of cells. Certain ion channels keep the heart beating rhythmically. Keating's group speculated that this gene, called HERG, plays a role in long QT syndrome.

To test that theory, they first demonstrated that HERG lies within the expected region of chromosome 7. "That's when it became a really exciting candidate," Keating says, although he ruefully acknowledges that other promising genes have not panned out.

Further research suggested that while HERG's protein product turns up on other cells of the body, it is usually found on the surface of heart cells.

Finally, the researchers identified HERG mutations in six families with long QT syndrome. They describe their results in the March 10 Cell.

The researchers believe that a flaw in HERG leads to a faulty potassium ion channel. Normally, this protein acts as a switch that turns contracting heart cells off. Without a functional potassium channel, these cells lack one of several "brakes" that keep the heartbeat under control. If another factor, such as stress or medication, knocks out the remaining brakes, the heart begins to race too fast to pump blood effectively.

"The engine of the heart goes galloping out of control," Keating says.

In a separate March 10 Cell report, Keating's team showed that a different gene, this one on chromosome 3, can also underlie long QT syndrome. This gene, called SCN5A, encodes a sodium ion channel, another regulatory protein on the surface of heart cells.

However, this gene's protein product appears to work as an accelerator. A mutant sodium channel thus gives heart cells an accelerator that is stuck in the "on" position, Keating says. This defect can also predispose people to develop a heart rhythm that can cause death within seconds.

The researchers describe a small mutation in SCN5A that appears in two families with this disorder.

Taken together, the flaws in HERG and SCN5A account for about 75 percent of all cases of long QT syndrome, the researchers believe.

Still other genes probably contribute to this disorder. Keating's group continues to search chromosome 11 for another such gene -- to no avail, so far.

The present discovery bodes well for people who know this disorder runs in their family, comments Robert Roberts at the Baylor College of Medicine in Houston. Many people with one of these genes go undiagnosed because they have normal-looking cardiograms. Researchers can now test the blood of individuals who have a family history of sudden death or fainting spells to see if they carry either of these mutant genes, says Roberts, a specialist in the molecular biology of the cardiovascular system. If so, doctors can start targeted treatment to counter the genetic flaw.

Hopefully, Roberts says, such therapy will prevent episodes of a runaway heart -- and death.