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A new gene responsible for arrhythmogenic right ventricular Cardiomyopathy


Arrhythmogenic right ventricular Cardiomyopathy (ARVC) is an inherited cardiac disease characterized by progressive fibro-fatty myocardial replacement, primarily of the right ventricle. Most of the pathogenic mutations in ARVC have been identified in genes encoding the desmosomal proteins plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2). Mutations in desmosomal genes have been identified in about 50% of the ARVC patients, defining desmosomes as major factors in ARVC pathogenesis (1-5).

The group of Padua (Italy), in collaboration with Ghent (Belgium), searched for new genes involved in ARVC according to a candidate gene approach in 76 patients with ARVC who did not carry any mutations in the desmosomal genes discussed above. They speculated that alphaT-catenin, encoded by CTNNA3, might be involved in pathogenesis of ARVC and analyzed this gene in the cohort of patients through denaturing high performance liquid chromatography and direct sequencing. They identified two mutations, c.281T>A (p.V94D) and c.2293_2295delTTG (p.del765L), in two probands. Each of the two mutations reported here affects crucial functions of alphaT-catenins. The authors performed various experimental studies to characterize the potential effects of the variants, after construction of wild type and mutant vectors, including yeast two-hybrid assay, transfection of different cells and immunofluorescent staining, immunoblot and co-immunoprecipitation.  Mutant p.V94D protein interacts only weakly with beta-catenin and plakoglobin, whereas the dimerization potential of mutant protein p.del765L is abnormally high, as  shown by yeast two-hybrid assay experiments and formation of aggresomes in transfected HEK293T cells.
Authors concluded that their findings suggest a causal relationship between CTNNA3 mutations and the ARVC pathology. 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.
Myocardial Disease


 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.



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Notes to editor

Presented by : Dr Philippe Charron,
Department of Cardiology, Pitié-Salpêtrière Hospital and Paris 6 University, Paris, France.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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