"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
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Contact: Scott Merville
scott.merville@uth.tmc.edu
713-500-3042
University of Texas Health Science Center at Houston
22-Jul-2005