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Gene’s Mutations Found to Cause Life-Threatening
Aortic Disease
Research may lead to earlier diagnosis and development of therapies for some aneurysms
Scientists have identified the first genetic mutations that cause the aorta – the body’s main artery – to widen, tear and rupture.
Dianna Milewicz, M.D., Ph.D.
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.
Aneurysm is a bulging of the aorta that leads to dissection, a lengthwise separation of tissues in the artery wall. Finding biological markers that flag aneurysm is critically important for early diagnosis.
Aneurysms can be managed initially with medication and then successfully repaired to prevent catastrophic dissection and rupture, said Milewicz, who holds the President George Bush Chair in Cardiovascular Medicine. 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 have 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.
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 who discover they are 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.
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.”
Milewicz’s team continues to scrutinize another genetic variation that may be involved in inheritance of aortic disease.
Milewicz and Raman also are on the faculty of the UT Graduate School of Biomedical Sciences at Houston, and Milewicz is a faculty member of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM).
Among the coauthors on the Circulation paper are first author Hariyadarshi Pannu, Ph.D., Van Tran Fadulu, Jessica Chang, Andrea Lafont and Sumera N. Hasham, Ph.D., all of the UT Medical School Department of Internal Medicine and the IMM; and Anthony Estrera, M.D., assistant professor, and Hazim Safi, M.D., professor and division chair of the UT Medical School Department of Cardiothoracic and Vascular Surgery. Additional co-authors are from Ohio State University, Marshfield Clinic, UT M. D. Anderson Cancer Center, and University of Iowa.
By Scott Merville, Public Affairs