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 3

Mice express Foxe3 in PAs during development, and Foxe3–/– mice have reduced medial cell density and total numbers of medial cells in the ascending aorta and aortic arch.

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Mice express Foxe3 in PAs during development, and Foxe3–/– mice have red...
(A) Expression of the Foxe3 transcription factor. Whole-mount ISH of WT mouse embryos (E9.5–E10.5) showed Foxe3 expression in the lens of the eye, in the forebrain/midbrain, and in the PAs; no expression was detected in the heart or its outflow tract. The higher-magnification image shows Foxe3 expression in PA1 and PA2, with weak expression in PA4. (B) Mouse aorta illustrates the regions of the aorta that were analyzed, indicating the ascending aorta, aortic arch, and DES1 and DES2. Original magnification, ×100. (C) Representative H&E-stained cross sections of ascending aorta, aortic arch, and descending aortae from male WT and Foxe3–/– mice at age P1, 4 weeks, and 6 months. (D) Bar graphs show that medial cell density (mean number of medial cell nuclei divided by the total medial area) and total number of medial cells per cross section of the ascending aorta, aortic arch, or descending aorta at day 1, 4 weeks, or 6 months of age were lower in the Foxe3–/– mice compared with WT mice. (E) Medial cell density and total number of medial cells were significantly lower in the ascending aortae and aortic arches in Foxe3–/– mice than in WT mice, but there was no statistical significant difference for the descending aorta. n = 5 per group. Error bars indicate SD from the average. *P < 0.05, by Student’s t test. Scale bars: 100 μm. ASC, ascending aorta.