A new gene responsible for arrhythmogenic right ventricular Cardiomyopathy

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 The paper nicely illustrates the role of genetics in providing some clues for a better understanding of the pathophysiology of ARVC. The candidate-gene approach is hypothesis-driven and has therefore many limitations but the present findings stronlgly support a causal relationship between the mutations and the disease. The co-segregation could not be established because of the small size of the families. The first mutation is described in a sporadic case as a de novo mutation. The second mutation is described in a sporadic case, and three relatives also carry the mutation including two with minor cardiac signs and one with a normal cardiac examination.  However the two heterozygous missense of CTNNA3  gene affect residues that are strongly conserved among species, the amino-acid change is predicted by software to be deleterious and the variants were absent from 250 ethnically matched healthy controls as well as from genome or exome variant data-bases. In addition experimental studies were performed and result support an effect on the protein or on its interactions with known partners such as beta-catenin and plakoglobin. The proof of a causal relationship between CTNNA3 mutations and ARVC awaits however the generation and analysis of appropriate animal models, including knock-in mice for the various CTNNA3 mutations.
 Area composita is a mixed-type junctional structure composed of both desmosomal and adherens junctional proteins (6). In epithelial cells, adherens junctions provide specific cell–cell adhesion by linking E-cadherin to the actin cytoskeleton. The cytoplasmic domain of E-cadherin binds the armadillo proteins beta-catenin and plakoglobin, which in turn bind alpha-catenins. Alpha-catenins are cytoplasmic molecules thought to be indispensable for dynamic maintenance of tissue morphogenesis by integrating in the cadherin–catenin complex and by interacting with the F-actin cytoskeleton. AlphaT-catenin is present in the area composita at the cardiac intercalated discs (ICD), as well as Ncadherin, one of the classic cadherins.
Most mutations known to cause ARVC are in JUP, DSP, PKP2, DSG2, and DSC2, all of which encode proteins present in both desmosomes and areae compositae. As alphaT-catenin is present only in areae compositae but not in desmosomes, ARVC could be considered a disease of the area composita rather than a classical desmosomal disease. This is an important finding of the present paper and suggests that additional proteins of the areae compositae might be be involved in and responsible for ARVC.