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 I3th 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 5qI3-14. 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: (1) to identity characterize, and collect samples from families with thoracic aortic aneurysms and dissections; (2) to identify the third locus for thoracic aortic aneurysms and dissections; (3) to narrow the critical interval at 5q 13-14 and identify candidate genes; (4) to screen for mutations in candidate genes using samples from families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections. The proposed studies will identify the defective gene at a major locus for thoracic aortic aneurysms and dissections. The mapping of a third locus responsible for the disease will be determined, which is the first step towards elucidating other gene defects responsible for this disease. 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL062594-01A2
Application #
6434793
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Wassef, Momtaz K
Project Start
2001-12-18
Project End
2006-11-30
Budget Start
2001-12-18
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$435,031
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Prakash, Siddharth K; Milewicz, Dianna M (2018) X Marks the Spot: The Profound Impact of Sex on Aortic Disease. Arterioscler Thromb Vasc Biol 38:9-11
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Guo, Dong-Chuan; Regalado, Ellen S; Pinard, Amelie et al. (2018) LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. Am J Hum Genet 102:706-712
Guo, Dong-Chuan; Hostetler, Ellen M; Fan, Yuxin et al. (2017) Heritable Thoracic Aortic Disease Genes in Sporadic Aortic Dissection. J Am Coll Cardiol 70:2728-2730
Milewicz, Dianna M; Trybus, Kathleen M; Guo, Dong-Chuan et al. (2017) Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections. Arterioscler Thromb Vasc Biol 37:26-34
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Milewicz, Dianna; Hostetler, Ellen; Wallace, Stephanie et al. (2016) Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 57:172-7
Jondeau, Guillaume; Ropers, Jacques; Regalado, Ellen et al. (2016) International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 9:548-558
Guo, Dong-chuan; Regalado, Ellen S; Gong, Limin et al. (2016) LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res 118:928-34
Karimi, Ashkan; Milewicz, Dianna M (2016) Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure. Can J Cardiol 32:26-34

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