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Gene's mutations found to cause life-threatening aortic disease

July 25, 2005

Scientists have identified the first genetic mutations that cause the aorta - the body's main artery - to widen, tear and rupture.

Published online by Circulation: Journal of the American Heart Association, the findings of a team led by University of Texas Medical School at Houston researchers shed new light on the molecular causes of thoracic aortic aneurysms and dissections. They also provide a new route for early warning of the condition, which builds slowly, usually with no symptoms, then often kills swiftly.

"We found that mutations in the Transforming Growth Factor Beta Receptor Type II (TGFBR2) caused aortic aneurysms and dissections in four families. This gives us a molecular pathway to study for development of therapies and for biological markers of the disease," said Dianna Milewicz, M.D., Ph.D., director of the UT Medical School Division of Medical Genetics and senior author of the paper.

Finding biological markers that flag aneurysm, a bulging of the aorta that leads to dissection, a lengthwise separation of tissues in the artery wall, is critically important for early diagnosis.

Aneurysms can be managed initially with medication and then successfully repaired to prevent catastrophic dissection and rupture, Milewicz said. Many patients never have a chance at treatment because they go undiagnosed, even when they go to emergency rooms with severe chest pain because diagnostic tests for heart attack do not uncover aortic defects. Actor John Ritter, for example, died in September 2003 from an undiagnosed dissection that ruptured.

Aortic aneurysms and dissections kill some 18,000 Americans every year. Research shows that 20 percent of those victims have close relatives who've had the disease.

Inherited aortic disease takes an unpredictable path, with some family members dying of a dissection in their 20s, others in their 70s. Study authors recommend that family members at risk of inheriting the defective gene undergo lifelong routine imaging of their aortas.

"Families with multiple members who have had thoracic aortic aneurysms and dissections should consider undergoing evaluation for these mutations," Milewicz said.

People carrying the TGFBR2 mutations should be advised to have their aorta routinely checked with advanced imaging techniques such as magnetic resonance or echocardiography. Preventive surgical repair should be undertaken when the ascending aorta's diameter approaches 5 centimeters, the study recommends.

Milewicz had earlier mapped this genetic variation to a portion of chromosome 3. In the present paper, researchers pinpointed the culprit gene as TGFBR2 by analyzing 80 families with a history of aneurysm and dissection. Four unrelated families had variations in the TGFBR2 gene that altered the structure of the protein and were connected to aneurysms, dissections and fatalities.

Structural analysis of the mutant TGFBR2 protein showed changes in a portion of the protein that hinder its ability to send and receive signals in its molecular pathway, said co-author C. S. Raman, Ph.D., assistant professor of biochemistry and director of the Medical School's Structural Biology Research Center.

"There are many proteins that turn this pathway off and regulate it," Milewicz said. "We are studying how the mutation changes the cell biology of the cells in the aorta."

The TGFBR2 pathway has long been studied in relation to cancer. Inactivation of the pathway has been shown to contribute to tumor formation and growth. Milewicz said the mutations connected to aortic aneurysm were not associated with cancer in the families studied. None of the families had symptoms of Marfan syndrome, a connective tissue disease that leaves its victims susceptible to aortic aneurysm and dissection.

"We know there are more genes involved in inheritance of aortic disease," Milewicz said. Milewicz's team continues to scrutinize a stretch of chromosome 5 to pinpoint another genetic variation that they earlier mapped to that area of the genome. Researchers elsewhere have mapped two other genetic variations affecting single families to chromosomes 11 and 16.

Milewicz also is on the faculty of the UT Graduate School of Biomedical Sciences at Houston and is appointed to the faculty of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM).

University of Texas Health Science Center at Houst