MAT2A mutations predispose individuals to thoracic aortic aneurysms

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Genetics

Background:

• Thoracic aortic disease (TAAD) often has a familial component, even in individuals without syndromic features.
• Genetic heterogeneity is a known factor in familial TAAD.
• Identifying specific genes is crucial for understanding disease mechanisms and inheritance patterns.

Purpose of the Study:

• To identify novel genes predisposing individuals to thoracic aortic aneurysms and dissections (TAAD).
• To investigate the role of the MAT2A gene in the pathogenesis of familial TAAD.

Main Methods:

• Whole-genome linkage analysis and exome sequencing were performed on families with autosomal-dominant TAAD.
• Rare variants in MAT2A were identified and segregated with the disease.
• Functional studies in zebrafish (morpholino knockdown and mRNA rescue experiments) were conducted.
• Population and structural analyses were used to assess variant significance.

Main Results:

• A rare variant (c.1031A>C, p.Glu344Ala) in MAT2A was identified in a large family with TAAD.
• Another rare MAT2A variant (c.1067G>A, p.Arg356His) was found in unrelated TAAD probands.
• These variants are conserved across species and impair MAT IIα enzyme function.
• MAT2A deficiency in zebrafish disrupted cardiovascular development, and human MAT2A variants failed to rescue these defects.

Conclusions:

• Rare genetic variants in MAT2A predispose individuals to thoracic aortic aneurysms and dissections.
• MAT2A variants disrupt methionine adenosyltransferase II alpha (MAT IIα) function, contributing to TAAD.
• This study expands the genetic landscape of thoracic aortic disease.