Mutations in the CTNNA3 gene (c.281T > A and c.2293_2295delTTG) were identified in two ARVC probands, suggesting a causal relationship between area composita gene mutations and ARVC pathogenesis.
Observational (n=76)
Are mutations in the CTNNA3 gene associated with arrhythmogenic right ventricular cardiomyopathy in patients without common desmosomal mutations?
Mutations in the CTNNA3 gene encoding αT-catenin are associated with ARVC, expanding the known pathogenesis of the disease beyond desmosomes to the area composita.
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes. METHODS AND RESULTS: We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c. 281T > A (p. V94D) and c. 2293₂295delTTG (p. del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p. V94D mutant protein and β-catenin was affected, whereas the p. del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. CONCLUSION: These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
Hengel et al. (Wed,) conducted a observational in Arrhythmogenic right ventricular cardiomyopathy (ARVC) (n=76). CTNNA3 mutations was evaluated on Identification of CTNNA3 mutations. Mutations in the CTNNA3 gene (c.281T > A and c.2293_2295delTTG) were identified in two ARVC probands, suggesting a causal relationship between area composita gene mutations and ARVC pathogenesis.