Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele
Abstract
Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder caused by mutations in desmosomal genes. It is often associated with life-threatening arrhythmias. Some affected individuals develop progressive heart failure and may require cardiac transplantation.
Methods
The explanted heart of a young adult with end-stage heart failure due to a null allele in desmoglein-2 was studied at macroscopic, microscopic, and molecular level. Myocardial samples were probed for junctional localization of desmosomal components and the gap junction protein connexin43 by immunohistochemical staining. In addition, the protein content of desmosomal and adherens junction markers as well as connexin43 was assessed by Western blotting.
Results
Histological analysis confirmed ARVC. Despite the loss of specific immunoreactive signal for desmosomal components at the cardiac intercalated disks (shown for plakoglobin, desmoplakin, and plakophilin-2), these proteins could be detected by Western blotting. Only for desmoglein-2, desmocollin-2, and plakoglobin were reduced protein levels observed. Adherens junction proteins were not affected. Lower phosphorylation levels were observed for connexin43; however, localization of the gap junction protein displayed regional differences. At the molecular level, disease progression was more severe in the right ventricle compared to the left ventricle.
Conclusion
Our data suggest that, in the ARVC heart, plakoglobin is mainly redistributed from the junctions to other cellular pools and that protein degradation only plays a secondary role. Homogenous changes in the phosphorylation status of connexin43 were observed in multiple ARVC samples, suggesting that this might be a general feature of the disease.
Keywords: Arrhythmogenic right ventricular cardiomyopathy, Desmosomal mutation, Desmoglein-2, Plakoglobin, End-stage heart failure, Cardiac transplant, Connexin43, Gap junction
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Sources of funding: This work was supported by the British Heart Foundation (program grant RG/04/010 to K.G., P.S., and W.J.M.), the Heart Rhythm Society (to A.A.), and the National Institutes of Health (HL102361 to J.E.S.). G.Q. is supported by a PhD Fellowship from the University “La Sapienza” of Rome and a European Society of Cardiology Research Fellowship. M.R. was supported by the European Commission ERASMUS Programme. Part of this work was undertaken at University College London/Hospital which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centre.
Conflict of interest: none declared.
PII: S1054-8807(11)00108-6
doi:10.1016/j.carpath.2011.09.005
© 2011 Elsevier Inc. All rights reserved.
