Pathological Study of a New ACTA2 Mutation Causing Aortic Aneurysm: Validation Using a Yeast Model

Research Background

Thoracic aortic aneurysm and dissection (TAAD) is a potentially fatal vascular disease with mechanisms that are still not fully understood. The ACTA2 gene encodes α-smooth muscle actin, a key component of the vascular smooth muscle contractile apparatus. Autosomal dominant variants of the ACTA2 gene are known to be associated with familial non-syndromic TAAD, and these variants have incomplete penetrance and variable phenotypes, making it complex to validate the pathogenicity of ACTA2 variants through family segregation studies. To address this issue, researchers developed a yeast-based assessment system to test potential TAAD-related ACTA2 variants.

Research Authors and Source

This study was jointly conducted by Cristina Calderan, Ugo Sorrentino, Luca Persano, Eva Trevisson, Geppo Sartori, Leonardo Salviati, and Maria Andrea Desbats. The research findings were published in the “European Journal of Human Genetics” in 2024.

Research Content

Research Process

Researchers identified five new heterozygous ACTA2 missense mutations in TAAD patients using Next Generation Sequencing (NGS) technology. The research team chose yeast actin, which is very similar to human α-smooth muscle actin, because the ACTA2 residues where TAAD-related variants occur are well conserved. The study used wild-type yeast strains transformed with a vector expressing different mutant alleles to simulate the heterozygous condition of patients. Subsequently, researchers evaluated yeast growth through spot assays and examined cytoskeleton and mitochondrial morphology using fluorescence microscopy.

Research Results

The experimental results showed that compared to the control group, the mutant yeast strains only displayed slight growth defects, but there was a significant increase in the percentage of abnormal mitochondrial distribution and actin cytoskeleton organization. All variants seemed to interfere with the activity of wild-type actin in yeast, exhibiting a dominant negative pathological mechanism for the corresponding variants. These results confirmed the effectiveness of using the yeast actin model system to validate the pathogenicity of ACTA2 variants associated with TAAD.

Research Conclusions and Significance

The conclusions of this study reinforce the utility of the yeast model system as a tool for testing the pathogenicity of ACTA2 variants. The scientific value of this research lies in providing a simple and powerful means for diagnosing genetic variants of TAAD, while also helping to non-invasively detect the health status of family members to prevent TAAD. Furthermore, the development of the yeast model provides a template for future functional validation of other genetic variants.

Research Highlights

The novelty of the research method lies in the first application of a yeast-based assessment system to validate ACTA2 genetic variants associated with aortic aneurysms. Moreover, the research addresses a highly significant issue, as TAAD is a life-threatening disease with mechanisms that are not yet fully understood.