Thoracic aortic aneurysms and dissections are the major diseases affecting the thoracic aorta and a common cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time and ultimately lead to acute aortic dissections (TAAD);if the aneurysm is surgically repaired prior to dissection premature deaths can be prevented. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 20% of TAAD patients (Familial TAAD). We have mapped five chromosomal loci for FTAAD and identified five genes that when mutated cause FTAAD, FBN1, TGFBR2, TGFBR1, ACTA2, and MYLK;other investigators have identified MYH11 as a sixth gene. Recently, family-based exome sequencing identified mutations in SMAD3 as the seventh gene causing FTAAD. In total, mutations in these genes are responsible for approximately 20% of FTAAD. Identification of these genes has provided insight into the pathogenesis of the disease, highlighting aberrant transforming growth factor-? signaling and disrupted smooth muscle contraction as factors contributing to TAAD. Correlation between mutations in specific genes and the corresponding phenotype has revealed unique features associated with each gene, leading to recommendation that disease management in FTAAD families be based on the specific genetic defect. We hypothesize that there are multiple genes responsible for familial TAAD, and this genetic heterogeneity underlies the significant clinical heterogeneity observed in FTAAD. The long term goal of the project is to identify the genes that cause FTAAD and characterize the associated phenotype.
The first aim i s to recruit families with two or more members with TAAD, collect samples, and characterize the clinical phenotype of these families.
The second aim i s to map chromosomal loci for FTAAD using large families with multiple affected members.
The third aim i s to identify novel FTAAD genes through exome sequencing of affected relative pairs from large families and combining these data with the linkage data to efficiently identify rare variants in disease-causing genes. Finally, initial pathologic, cellular, and molecular studies will be done to begin to understand the effect of gene mutations on aortic function. Through these studies, we will improve understanding of the etiology of aortic diseases and provide data critical for the proper clinical management of familia thoracic aortic disease.
Acute aortic dissections are a common cause of premature death in the United States, ranking as high as the 15th leading cause of death. The goal of the proposed research is to prevent premature deaths due to aortic dissections by identifying individuals who are genetically predisposed to the disease and initiating medical and surgical therapies to prevent dissections.
|Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303|
|Tan, Kai Li; Haelterman, Nele A; Kwartler, Callie S et al. (2018) Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms. Dev Cell 45:226-244.e8|
|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|
|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|
|Regalado, Ellen S; Mellor-Crummey, Lauren; De Backer, Julie et al. (2018) Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med 20:1206-1215|
|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|
|Liu, Zhenan; Chang, Audrey N; Grinnell, Frederick et al. (2017) Vascular disease-causing mutation, smooth muscle ?-actin R258C, dominantly suppresses functions of ?-actin in human patient fibroblasts. Proc Natl Acad Sci U S A 114:E5569-E5578|
|Chen, Jiyuan; Peters, Andrew; Papke, Christina L et al. (2017) Loss of Smooth Muscle ?-Actin Leads to NF-?B-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement. Circ Res 120:1903-1915|
|Milewicz, Dianna M; Prakash, Siddharth K; Ramirez, Francesco (2017) Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models. Annu Rev Med 68:51-67|
|Humphrey, Jay D; Milewicz, Dianna M (2017) Aging, Smooth Muscle Vitality, and Aortic Integrity. Circ Res 120:1849-1851|
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