FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.

Area of Science:

• Genetics
• Cardiovascular Biology
• Molecular Biology

Background:

• Thoracic aortic aneurysms and acute aortic dissections (TAADs) result from genetic defects affecting aortic structure and biomechanical force response.
• The ascending thoracic aorta relies on structural integrity to manage pulsatile blood flow.
• Understanding the genetic underpinnings of TAAD is crucial for developing effective treatments.

Purpose of the Study:

• To identify novel genetic factors contributing to familial thoracic aortic disease.
• To elucidate the role of the forkhead transcription factor FOXE3 in aortic development and disease pathogenesis.
• To investigate the molecular mechanisms by which FOXE3 mutations lead to TAAD.

Main Methods:

• Exome sequencing was employed to identify genetic variants in families with a history of TAAD.
• Functional studies in mice, including gene deficiency models and surgical aortic constriction, were performed.
• Pharmacological inhibition and genetic knockout of p53 were used to assess its role in FOXE3-related phenotypes.

Main Results:

• Pathogenic variants in the FOXE3 gene were identified in multiple families with TAAD, segregating with the disease.
• Foxe3 deficiency in mice led to reduced smooth muscle cell density, impaired differentiation, and increased apoptosis in the ascending aorta.
• Foxe3 deficiency resulted in increased susceptibility to aortic rupture under elevated pressure, a phenotype rescued by p53 inhibition or knockout.

Conclusions:

• FOXE3 mutations represent a novel genetic cause of familial thoracic aortic disease.
• FOXE3 plays a critical role in maintaining aortic smooth muscle cell homeostasis and integrity.
• Targeting the p53 pathway may offer a therapeutic strategy for FOXE3-associated aortic diseases.