Losing Rhythm: Gene mutation causes heart problems

Chinese researchers have for the first time identified a genetic defect that causes atrial fibrillation, a heart condition that afflicts 5 percent of people over 65 years old. In the disorder, the heart’s upper chambers, the atria, beat irregularly and too rapidly. Ultimately, this arrhythmia can cause heart failure or dangerous blood clots.

“Atrial fibrillation is the most common rhythm disturbance of the heart. It accounts for one-third of all strokes [in people] over the age of 65,” says cardiologist Robert Roberts of Baylor College of Medicine in Houston.

The defect causing the heart disease is on chromosome 11, the researchers report in the Jan. 10 Science. The affected gene encodes a protein, called KCNQ1, that joins with another protein to form pores regulating the flow of potassium ions in and out of cells. In this way, these so-called ion channels govern the electrical excitability of cells that make the heart beat.

By studying four generations of a family in which 16 of 44 members have the heart disorder, a research team led by Yi-Han Chen of Tongji University and Shi-Jie Xu of the Chinese National Human Genome Center, both in Shanghai, linked the gene for KCNQ1 to atrial fibrillation. The investigators discovered that only those family members with atrial fibrillation have a subtle misspelling of the gene’s normal DNA sequence.

This defect changes an amino acid within KCNQ1 from a serine to a glycine.

“This is a major finding,” says Roberts. “This gives an opportunity to understand how a single molecule that is only changed by one amino acid can induce atrial fibrillation.”

Researchers had previously connected defects in channels for potassium, sodium, and calcium ions to several other heart disorders (SN: 3/11/95, p. 149). In fact, scientists already knew that mutations that completely disable the gene for KCNQ1 produce a heart condition called long QT syndrome, which predisposes a person to sudden death.

The mutant gene from the Chinese family produces an ion channel that stays open longer than usual, Chen, Xu, and their colleagues found in lab studies. The researchers suggest that the abnormal inrush of potassium disrupts the heart’s typical rhythm, leading to atrial fibrillation.

Most atrial fibrillation stems from nongenetic causes, such as infections or preexisting heart disease. An initial survey of 19 people who have atrial fibrillation but no family history of the disorder hasn’t revealed mutations in the gene for KCNQ1. Nevertheless, Roberts suggests that drugs that alter the function of KCNQ1 could help people with atrial fibrillation from various causes.


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