Researchers have linked two serious causes of heart valve disease by discovering mutations in a particular gene that appear to be responsible for both of them. The mechanism by which the mutations cause the defects strongly suggests that the gene might also be involved in an adult-onset form of the disease. If so, variations in the gene might predict who will come down with stiffened heart valves later in life.
As people get older, their aortic valves can begin to collect hard nodules of calcium and may eventually become stiff and inoperative. Other types of heart valve disease arise at birth: Some individuals are born with an abnormal valve that has only two flaps instead of the typical three--which often goes undetected until calcium deposits stiffen them--and some infants are born with malformed hearts due to calcium clogging the aorta while the heart develops in utero. Because the two congenital abnormalities tend to run in the same families, pediatric cardiologist Deepak Srivastava, then at the University of Texas Southwestern Medical Center in Dallas, and colleagues wanted to find the gene responsible.
First, the team located two families that had members with either the congenital defect or the missing valve. By tracing variations in their DNA that were passed through several generations along with the defects, the researchers found that a mutation in a gene called NOTCH1 was the most likely culprit for the disorders.
Using biochemical methods, Srivastava's group showed that NOTCH1 controls calcium pumping. That's important because, in the aortic valve diseases, heart cells inappropriately pump out calcium. Even more intriguing, the team discovered that the mutant protein failed to stop cells from spewing calcium into the valve cells of mouse heart tissue. This suggested that variations of the human NOTCH1 gene could affect its activity. Because the calcium regulation defect seen in the two disorders also resembles that seen in the adult-onset form of the disease, the researchers believe all three may be linked.
"This work provides a direct connection between congenital defects and acquired heart disease late in life," says pediatric cardiologist D. Woodrow Benson at the Cincinnati Children's Hospital Medical Center in Ohio. If researchers can show that particular NOTCH1 sequences result in calcified heart valves in older adults, "we will have a chance to identify people who are at risk of developing heart disease. Now for the first time we can think about prevention."