FOXE3 mutations predispose to thoracic aortic aneurysms and dissections
Shao-Qing Kuang, … , Milan Jamrich, Dianna M. Milewicz
Shao-Qing Kuang, … , Milan Jamrich, Dianna M. Milewicz
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):948-961. https://doi.org/10.1172/JCI83778.
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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 1

Identification of FOXE3 mutations as a cause of FTAADs.

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Identification of FOXE3 mutations as a cause of FTAADs. (A) Pedigree of ...
(A) Pedigree of family TAA337, with the legend showing the designation of the disease and mutation status of the family members. The age at diagnosis of aortic root enlargement and/or dissection (dx.) is shown in years, and “d.” indicates age at death. The diagonal line across the symbol indicates that the individual is deceased. DNA from the individuals circled in red was used for exome sequencing. (B) Ascending aortic pathology in individual III:12 from family TAA337 and control aorta. H&E and Movat pentachrome staining of ascending aortic media from III:12 demonstrated loss of SMCs (red in Movat stain) between intact elastin fibers (black; original magnification, ×400). (C) Pedigree of MS300 with a FOXE3 p.Gly137Ala mutation. (D) Schematic representation of FOXE3 protein domain structure and location of rare variants. The FOXE3 rare variants identified in this study are on the top of the protein diagram. Red color indicates variants likely to be pathogenic for FTAAD. The FOXE3 mutations that were reported to be causative for ocular lens abnormalities are on the bottom of protein diagram. Blue color indicates dominant mutations; green color indicates recessive mutations.