FOXE3 mutations predispose to thoracic aortic aneurysms and dissections
Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Investigators, National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) Exome Sequencing Project (ESP), Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz
Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Investigators, National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) Exome Sequencing Project (ESP), Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz
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Research Article Vascular biology

FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

Abstract

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3–/– mice with p53–/– mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

Authors

Shao-Qing Kuang, Olga Medina-Martinez, Dong-chuan Guo, Limin Gong, Ellen S. Regalado, Corey L. Reynolds, Catherine Boileau, Guillaume Jondeau, Siddharth K. Prakash, Callie S. Kwartler, Lawrence Yang Zhu, Andrew M. Peters, Xue-Yan Duan, National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Investigators, National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity (GO) Exome Sequencing Project (ESP), Michael J. Bamshad, Jay Shendure, Debbie A. Nickerson, Regie L. Santos-Cortez, Xiurong Dong, Suzanne M. Leal, Mark W. Majesky, Eric C. Swindell, Milan Jamrich, Dianna M. Milewicz

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Figure 4

Foxe3–/– ascending aortae have reduced expression of SMC genes encoding contractile protein but show no difference in proliferating or TUNEL-positive cell levels compared with WT controls.

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Foxe3–/– ascending aortae have reduced expression of SMC genes encoding...
(A) Anti–p-H3 staining (p-H3, for proliferative cells) of representative cross sections of ascending aortae from WT and Foxe3–/– mice at 4 weeks and 6 months of age. The cellular proliferation marker showed no differences between WT and Foxe3–/– aortae from mice of the same age. Scale bars: 100 μm. (B) TUNEL staining in ascending aortic sections from WT and Foxe3–/– mice at 4 weeks and 6 months of age. No differences in the percentage of TUNEL-positive cells were observed in aortae from WT and Foxe3–/– mice of the same age. Scale bars: 100 μm. Error bars indicate SD from the average. (C) Real-time qPCR analysis of SMC differentiation marker genes (Acta2, Myh11, Cnn1, and Tagln) using RNA from ascending and descending aortic tissues from WT and Foxe3–/– mice (expression levels were normalized to Gapdh). n = 5 per group. **P < 0.01, by Student’s t test. (D) Western blots for the SMC contractile proteins α-SMA, smooth muscle myosin heavy chain (SM-MHC), and calponin (CNN1) in ascending aortae, thoracic descending aortae, and explanted ascending aortic SMCs from WT and Foxe3–/– mice. Bar graphs show densitometric quantification for α-SMA, SM-MHC, and CNN1 in ascending aortae, descending aortae, and SMCs from WT and Foxe3–/– mice. Protein levels were significantly lower in the ascending aortae and explanted SMCs from Foxe3–/– mice compared with levels detected in WT mice, but there was no difference in levels in the descending aortae. n = 5 per group. *P < 0.05, by Student’s t test. Error bars indicate SD from the average. DES, descending aorta.