President George H.W. Bush Chair of Cardiovascular Medicine

Professor
Director of Medical Genetics
The University of Texas Medical School at Houston

For more information

• Dr. Milewicz's biography
• Contact Dr. Milewicz
• About The University of Texas Medical School at Houston
• About Medical Genetics

About the presentation

"Aortic Aneurysms and Dissections: Using Genetics to Unravel Pathways to These Fatal Diseases"
The aorta is the major vessel of the body carrying blood from the heart to arteries throughout the body. When weakened by disease, the wall of the aorta may dilate, producing an aneurysm, or may split along its long axis, bringing about an aortic dissection. Both alterations can lead to rupture of the aorta with life-threatening consequences.

Twenty percent of thoracic aortic aneurysms and dissections (TAAD) result from a genetic predisposition to the disorder, which is inherited in families in an autosomal dominant manner with decreased penetrance and variable expression. Research in Milewicz's lab has focused on identifying the genes that predispose individuals to aortic disease with the long-term goal of preventing premature deaths due to aortic dissection and rupture, and increasing our understanding of the molecular pathogenesis of these aortic diseases.

Milewicz has recruited and characterized over 300 families with multiple members with thoracic aortic aneurysms and dissections and used DNA from these families to map genes that cause this disorder. Familial aortic disease demonstrates significant genetic heterogeneity, and her linkage studies have identified four loci for the disease, 5q13-14 (TAAD1), 11q23 (FAA1), 3p24-25 (TAAD2), and 15q (TAAD3). The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features.

Recently, mutations in the gene for transforming growth factor beta receptor type II (TGFBR2) have been identified as the cause of disease at the TAAD2 locus, suggesting that dysregulation of TGF-β signaling is a mechanism leading to aneurysms and dissections. This information has opened new avenues to identify mutant genes causing familial aortic aneurysms and dissections and has the potential to elucidate molecular therapeutic targets to prevent these diseases.