Specific Gene Mutations Responsible For Heart Problems

By studying five generations of a Dallas family, University of Texas researchers have discovered that a mutation in a key gene causes aortic valve disease, a common heart birth defect, and a major contributor to adult heart disease.

In the trial, researchers scanned the DNA of 11 members of a family that was affected with aortic heart disease. The patients ranged from children with severe narrowing of the aortic valve to 50- and 60-year-olds who had calcium buildup on their heart valves severe enough to warrant replacement valves.

The researchers found that all the relatives with some manifestation of aortic valve disease had a mutation in a gene called Notch 1.

A second, smaller family with the heart disorder in San Diego, California, also had members with a second mutation in the same gene, providing convincing evidence that the researchers had found the genetic link to aortic heart disease, said Dr. Vidu Garg, lead author of the study.

"Mutations in Notch 1 cause an early developmental defect in the aortic valve," he explained.

The aortic valve is located between the left ventricle (the lower chamber of the heart) and the largest artery (the aorta). The left ventricle pumps oxygen-rich blood into the aorta, which carries blood to the brain and the rest of the body.

The normal aortic valve is made up of three leaflets, flaps of tissue that open and close to allow blood flow through the valve in only one direction. About 1 to 2 percent of the world's population is born with only two valve leaflets, a defect called bicuspid aortic valve. The condition predisposes individuals to aortic valve stenosis, which severely narrows the passage for blood to exit the heart and, in many cases, requires surgery at birth.

The narrowing of the valve can be so severe while the fetus is still developing that blood cannot get out of the ventricle. In those cases, the ventricle does not grow, and the child is born with a condition called hypoplastic left-heart syndrome.

"The left ventricle of these children is almost nonexistent, and they are born with one of the most severe types of congenital heart disease, which accounts for a quarter of all children who die from heart disease," said Dr. Deepak Srivastava, senior author.

"We know that aortic valve problems cause those deaths, so we think Notch 1 mutations are likely the cause of some cases of hypoplastic left heart syndrome as well," he said.

Many people born with bicuspid aortic valve go on to develop early calcification, or hardening, of the aortic valves, which is the third most common cause of heart disease in adults. As calcium deposits build up on the valve, the leaflets do not open normally, and the heart's ability to supply blood to the body decreases. Eventually, the valve must be replaced.

"Our work suggests that calcification of the aortic valve may be a manifestation of a mutation in Notch 1 or related genes," Dr. Garg said. "In the long term, we may be able to use that information to screen those at risk, possibly giving patients the opportunity to make a pharmacological or lifestyle intervention to slow down the progression of the calcification. I think that's where the clinical utility of this research will most likely be."

To identify possible therapeutic agents, further study is needed to determine exactly how the gene leads to calcification.

"Because of these families, we found that the Notch 1 protein normally shuts down factors that control bone development, and this may provide clues for understanding why tissues become abnormally calcified in the setting of disease," Dr. Srivastava said.

(Source: Nature, 2005;437:270-274.)

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