Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele.
BACKGROUND
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.


CONCLUSIONS
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.
Institute of Cardiovascular Science and The Heart Hospital, University College London, United Kingdom. katja.gehmlich@cardiov.ox.ac.uk
Katja
K
Gehmlich
Petros
P
Syrris
Mareike
M
Reimann
Angeliki
A
Asimaki
Elisabeth
E
Ehler
Alison
A
Evans
Giovanni
G
Quarta
Antonis
A
Pantazis
Jeffrey E
JE
Saffitz
William J
WJ
McKenna
D000293:Adolescent; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015153:Blotting, Western; D019556:COS Cells / Q000378:metabolism; D002522:Chlorocebus aethiops; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D051301:Desmoglein 2 / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D014162:Transfection; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism
D018031:Connexin 43; C495314:DSG2 protein, human; D051301:Desmoglein 2; C500216:GJA1 protein, human; D051185:gamma Catenin