CTNNA3 – Arrhythmogenic Right Ventricular Cardiomyopathy

The CTNNA3 gene has been implicated in autosomal dominant Arrhythmogenic right ventricular cardiomyopathy. In a cohort of 76 ARVC patients without known desmosomal mutations, two unrelated probands carried CTNNA3 variants c.281T>A (p.Val94Asp) and c.2293_2295delTTG (p.Leu765del) (PMID:23136403). No additional segregation data are reported. A prior screen of 65 unrelated ARVC cases found no pathogenic CTNNA3 mutations, suggesting a low but nonzero mutation frequency in ARVC (PMID:21254927).

Functional assays demonstrate that the p.Val94Asp mutant impairs binding to β-catenin, whereas the p.Leu765del allele shows enhanced homodimerization and aggresome formation in HEK293T cells, consistent with a dominant-negative mechanism of disease (PMID:23136403). These data support a role for CTNNA3 in maintaining cardiomyocyte adhesion at the area composita. Systematic inclusion of CTNNA3 in ARVC genetic testing may improve diagnostic yield. Key Take-home: CTNNA3 variants provide limited but supportive evidence for involvement in ARVC and merit consideration in clinical panels.

References

• Genetic testing and molecular biomarkers • 2011 • Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy PMID:21254927
• European Heart Journal • 2013 • Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy PMID:23136403

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