FOXE3 mutations predispose to thoracic aortic aneurysms and dissections

J Clin Invest. 2016 Mar 1;126(3):948-61. doi: 10.1172/JCI83778. Epub 2016 Feb 8.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aneurysm, Dissecting / genetics*
  • Aneurysm, Dissecting / metabolism
  • Aneurysm, Dissecting / pathology
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Aneurysm, Thoracic / genetics*
  • Aortic Aneurysm, Thoracic / metabolism
  • Aortic Aneurysm, Thoracic / pathology
  • Apoptosis
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • Forkhead Transcription Factors / genetics*
  • Gene Expression
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular / pathology
  • Mutation, Missense
  • Myocytes, Smooth Muscle / physiology
  • Pedigree
  • Tumor Suppressor Protein p53 / genetics
  • Vascular Remodeling
  • Zebrafish

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • FOXE3 protein, human
  • Forkhead Transcription Factors
  • Tumor Suppressor Protein p53