DALLAS, Dec. 22 -- A gene for an inherited heart disorder that accounts for a significant number of sudden deaths and heart failure in young people has been located -- or mapped -- by U.S. and Canadian researchers, who report their research in today's Circulation: Journal of the American Heart Association. The gene, found on chromosome 3, is responsible for a heart condition called arrhythmogenic right ventricular dysplasia (ARVD), says the study's lead author, Robert Roberts, M.D., professor of medicine and cell biology at Baylor College of Medicine in Houston.
"It should be possible to isolate and clone -- or reproduce -- the gene and identify the mutation within two years," says Roberts. Cloning the ARVD gene should help scientists better understand this puzzling heart disorder, Roberts says. It should also offer important insights into broader questions regarding sudden-death heart attacks -- in which death occurs within hours -- and heart failure, a severe weakening of the heart's ability to pump blood.
Roberts and his colleagues located the ARVD gene by studying the genetic family tree of a North American family through seven generations. They had information on more than 200 members of the family, including 10 who were living and diagnosed with ARVD. They obtained blood samples from 149 family members of the 10 living individuals and linked the mutant gene that causes ARVD in the family to chromosome 3.
ARVD strikes about 1 in 5,000 people and accounts for about 15 percent of sudden deaths in young people, say researchers. It is an autosomal dominant disease, which means a person needs to inherit a defective gene from only one parent to develop the disorder. Children and young adults with ARVD have a 2.5 percent chance of dying in any year.
The disease is difficult to diagnose. Often, the first symptom of ARVD is death, triggered by erratic heartbeats called arrhythmias. Those who do not suffer sudden death develop symptoms of heart failure -- including swelling of the hands and feet and shortness of breath -- in their 30s and 40s, and usually die within a few years.
In ARVD, the heart muscle in the right ventricle, the side of the heart that pumps blood to the lungs, dies and is replaced by fat cells and fibrous tissue. The muscle cells die because of an unknown defect in the body's natural system of programmed cell death, called apoptosis, in which the body rids itself of malfunctioning cells.
"This is an unusual disease because the muscle cells of the ventricle actually die," he adds. "The problem here is a defect in one of the mechanisms of apoptosis, which is the subject of major research all over the western world right now. If we can find the mechanism of this defect, it would help unlock the process of programmed cell death."
Now the race is on to clone the gene and devise a simple test that will tell family members of individuals with ARVD whether they too have inherited this specific faulty gene. Some members of the tested family already have had automated defibrillators implanted in their bodies to try to protect themselves against sudden bursts of fatal arrhythmias.
The ARVD gene lies on a stretch of 7 million base pairs of DNA (the chemical component of the gene), which comprise perhaps 150 genes. Of these genes, only a few are likely to be active in the heart. The researchers will first determine which genes are expressed in the heart and then examine these genes for a single gene mutation that is shared by family members who have ARVD. "Once we find a mutation, then we can just take a blood sample and make the diagnosis," says Roberts. "The technology is moving so fast in genetics that if we get any luck at all we could have it cloned within a year. We are certainly putting a lot of effort into it.
"By finding the cause of an inherited disease we can design targeted therapies and understand similar diseases that cause sudden death and heart failure," Roberts says.
He cites as an example the unraveling of the genetics of familial hypercholesterolemia, a rare inherited form of heart disease that is characterized by high blood levels of cholesterol in young people. This finding helped to define the role of cholesterol metabolism in heart attacks. Scientists are intrigued by the fact that ARVD occurs only in the right ventricle. Two other inherited heart disorders that can cause sudden and early death occur only in the larger left ventricle, which pumps blood to the rest of the body. This ventricle-specific occurrence mystifies researchers.
"As far as we know, the same genes are found in the right ventricle as the left ventricle," Roberts says. "The gene may not be present in one of the ventricles, but this is unlikely. The most likely reason is that the gene's interaction with the right ventricle is different than if it were in the left. If we can find the gene, we should be able to confirm this."
Co-authors of the paper are Ferhaan Ahmad, M.D.; Duanxiang Li, M.D.; Akihiko Karibe, M.D., Ph.D.; Oscar Gonzalez, B.S.; Terry Tapscott, B.S.; Rita Hill, B.S.N.; Donald Weibaecher, M.D.; Peter Blackie, M.D.; Michael Furey, M.D.; Martin Gardner, M.D.; and Linda L. Bachinski, Ph.D.
Materials provided by American Heart Association. Note: Content may be edited for style and length.
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