Biography
Dianna M. Milewicz, M.D. Ph.D., is Professor and Vice Chairman of the Department of Internal Medicine at The University of Texas Medical School at Houston. She is Director of the M.D./Ph.D. Program and co-Director of the Biomedical Engineering Center, both of which are joint programs between The University of Texas Health Science Center at Houston and M.D. Anderson Cancer Center. Her research interests include the genetic basis of cardiovascular diseases, and understanding the effect of identified mutations on protein function. She has recently established a genetic core laboratory to provide molecular biology and genetic expertise to clinicians who want to initiate genetic studies on their patient populations.
Dr. Milewicz graduated from Rice University, received her M.D. and Ph.D. from The University of Texas Southwestern Medical School, and completed her residency in internal medicine at the same institution. She did her fellowship training in medical genetics at the University of Washington Medical School and joined the faculty at The University of Texas Medical School at Houston in 1991. Dr. Milewicz’s awards include a Pfizer Scholars Award, March of Dimes Basil O'Connor Scholar Award, American Heart Association Established Investigator Award, membership in the American Society of Clinical Investigation (ASCI), and the 1999 Antoine Marfan Award from the National Marfan Foundation. She is an Associate Editor of Circulation and a member of the National Marfan Foundation Professional Advisory Board.
Abstract
Genetic Basis of Aortic Aneurysms and Dissections
The major disease processes affecting the aorta are aortic aneurysms and dissections. Aortic aneurysms are a major health problem in the United States, representing the 13th major cause of death, accounting for nearly 15,000 deaths annually. Ten to twenty percent of all aneurysms result from a genetic predisposition for the disorder. Although some familial aneurysms are due to inherited defects in extracellular matrix proteins, including Marfan syndrome and Ehlers-Danlos syndrome type IV, the majority of inherited aneurysms occur as an isolated cardiovascular abnormality, segregating in families as a monogenic autosomal dominant disorder. We have identified 25 families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections, in whom the disease is characterized by variable expression and decreased penetrance. Using DNA obtained from family members and polymorphic markers spaced throughout the human genome, we have mapped a defective gene causing the disorder in 12 of these families to 5 Mb region at 5q13-14. Dr. Craig Basson and his colleagues (Cornell University Medical College) have mapped a second locus for familial aneurysms in one large family to 11q23. We have confirmed further genetic heterogeneity for this disorder by the identification of families in whom the inheritance of the phenotype is not linked to the two identified loci. The long-term goal of the proposed project is to identify the mutant genes that predispose an individual to thoracic aortic aneurysms or dissections.
The specific aims are the following:
- to identify, characterize, and collect samples from families with thoracic aortic aneurysms and dissections;
- to narrow the critical interval at 5q13-14 and identify candidate genes;
- to screen for mutations in candidate genes using samples from families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections;
- to characterize mutations in sporadic cases of thoracic aortic aneurysms and dissections.
The proposed studies will identify the defective gene at a major locus for thoracic aortic aneurysms and dissections. Identification of the genetic etiology of aortic aneurysms and dissections will enable preclinical diagnosis in families at risk. In addition, identification of the defective genes will lead to the development of experiment models of vascular pathology to increase understanding of the molecular pathology and provide the basis for rationale intervention.