Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Cell Adhesion

Background:

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary cause of sudden cardiac death in young individuals, characterized by fibro-fatty tissue replacement in the right ventricle.
• Genetic mutations in desmosomal proteins are established causes of ARVC.
• Alpha-T-catenin (αT-catenin), a protein involved in cell adhesion via the area composita, is encoded by the CTNNA3 gene.

Purpose of the Study:

• To investigate the potential role of CTNNA3 gene mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients.
• To explore the functional consequences of identified CTNNA3 mutations on αT-catenin protein function.

Main Methods:

• Screening of the CTNNA3 gene in 76 ARVC patients negative for mutations in common desmosomal genes using denaturing high-performance liquid chromatography and direct sequencing.
• Functional analysis of mutant αT-catenin proteins using yeast two-hybrid assays and cell transfection studies in HEK293T cells.

Main Results:

• Two pathogenic mutations, c.281T > A (p.V94D) and c.2293_2295delTTG (p.del765L), were identified in the CTNNA3 gene in two ARVC probands.
• The p.V94D mutation impaired the interaction between αT-catenin and β-catenin.
• The p.del765L mutation resulted in increased protein dimerization and aggresome formation.

Conclusions:

• The identified CTNNA3 mutations suggest a potential causal link between CTNNA3 and ARVC.
• This study broadens the genetic basis of ARVC, indicating that genes involved in the area composita, not just desmosomes, play a role in the disease.
• Systematic screening of CTNNA3 is recommended for improved diagnosis and management of ARVC families due to its non-rare mutation frequency.