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Mutation in the SCN5A sodium-channel gene slows heart rate
By Bijal P. Trivedi

Scientists have identified a tiny variation in the SCN5A sodium-channel protein that can disrupt the heart's electrical activity and lead to a dramatic slowing of heart rate. The protein is basically a donut-shaped molecule through which sodium travels into the cell. The researchers have identified a genetic mutation that underlies the defective sodium channel, and they report that a steroid can be used in combination with a pacemaker to help normalize the heartbeat.

A team of Dutch and American researchers first identified the SCN5A mutation in a 3-year-old girl who was hospitalized in The Netherlands after fainting repeatedly during a fever. Doctors found that the girl's heart rate was only about 25 beats per minute (130 beats per minute is normal at that age). The researchers identified four other family members with abnormal rhythms, including a 6-year-old sister whose heart rate was also severely reduced. Testing showed that the problem was not due to a structural heart defect.

Jeffrey R. Balser, of Vanderbilt University School of Medicine in Tennessee, and colleagues suspected that a mutation in the sodium-channel gene might be responsible for the slow heart rate in the Dutch family. A number of mutations in this gene are associated with sudden episodes of rapid heart rhythms.

Balser's team sequenced the SCN5A gene in the five affected family members and in 200 healthy individuals. The researchers traced the mutation to a location in the gene where a nucleotide guanine had been changed to thymine. The mutation alters the sodium channel by replacing the amino acid glycine at position 514 of the protein with cysteine. This amino acid change has the potential to dramatically affect the structure of the channel, and the researchers show that the mutant channel fails to open and close normally.

When the channel is open, sodium flows through and generates an electrical current. The mutant channel does not open normally and generates less current. It is the opening and closing of these channels that creates the electrical impulses that make the heart beat.

"These mutant channels are like teenagers in the morning—they need a little encouragement," says Balser. The 'encouragement' comes from a pacemaker that sends electrical impulses that force the channels to open properly. The pacemaker failed to normalize the heartbeats, however, until the sisters received steroid treatments. How the steroid improves the functioning of the mutant sodium channel is not known. The findings appear in the current issue of Nature.

While the mutation found in the Dutch family is rare, millions of people have conduction defects that slow the heart rate and require the use of a pacemaker. Balser intends to investigate whether the SCN5A gene is involved with conduction defects in older people. Balser will also focus on genes and other factors that disrupt sodium-channel functions.

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Tan, H. L. et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 409, 1043-1047 (February 22, 2001).

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