COL5A1 Variants Cause Aortic Dissection by Activating TGF-β-Signaling Pathway

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Pathology

Background:

• Aortic dissection (AD) is a life-threatening cardiovascular disease with significant genetic heterogeneity.
• The role of variants in the COL5A1 gene in causing AD remains unclear.
• This study investigates COL5A1 as a potential causative gene for AD.

Purpose of the Study:

• To determine if variants in the COL5A1 gene are causative for aortic dissection (AD).
• To investigate the underlying mechanisms of COL5A1-associated AD.

Main Methods:

• Targeted sequencing of 152 vessel matrix-related genes in 702 sporadic AD patients and 163 controls.
• Generation of Col5a1 knockout rats using CRISPR/Cas9.
• Induction of AD phenotype in rats using β-aminopropionitrile monofumarate and angiotensin II.

Main Results:

• Eleven COL5A1 variants were identified in 1.57% of sporadic AD patients.
• Col5a1 knockout rats exhibited disrupted elastic and collagenous fibers.
• Col5a1 knockout rats showed a significantly higher incidence of AD after induced stress compared to wild-type rats.
• The transforming growth factor-β signaling pathway was activated in Col5a1 knockout rats.

Conclusions:

• This study identifies COL5A1 variants as a cause of sporadic aortic dissection in a subset of patients.
• Col5a1 knockout rats develop AD-like pathology, confirming COL5A1 as a causative gene.
• Activation of the transforming growth factor-β signaling pathway is implicated in the pathogenesis of COL5A1-related AD.