Elsevier

Heart Rhythm

Volume 8, Issue 5, May 2011, Pages 711-718
Heart Rhythm

Clinical
Genetic
A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions

https://doi.org/10.1016/j.hrthm.2011.01.010Get rights and content
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Background

Cellular adhesion mediated by cardiac desmosomes is a prerequisite for proper electric propagation mediated by gap junctions in the myocardium. However, the molecular principles underlying this interdependence are not fully understood.

Objective

The purpose of this study was to determine potential causes of right ventricular conduction abnormalities in a patient with borderline diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Methods

To assess molecular changes, the patient's myocardial tissue was analyzed for altered desmosomal and gap junction (connexin43) protein levels and localization. In vitro functional studies were performed to characterize the consequences of the desmosomal mutations.

Results

Loss of plakoglobin signal was evident at the cell junctions despite expression of the protein at control levels. Although the distribution of connexin43 was not altered, total protein levels were reduced and changes in phosphorylation were observed. The truncation mutant in desmocollin-2a is deficient in binding plakoglobin. Moreover, the ability of desmocollin-2a to directly interact with connexin43 was abolished by the mutation. No pathogenic potential of the desmoglein-2 missense change was identified.

Conclusion

The observed abnormalities in gap junction protein expression and phosphorylation, which precede an overt cardiac phenotype, likely are responsible for slow myocardial conduction in this patient. At the molecular level, altered binding properties of the desmocollin-2a mutant may contribute to the changes in connexin43. In particular, the newly identified interaction between the desmocollin-2a isoform and connexin43 provides novel insights into the molecular link between desmosomes and gap junctions.

Keywords

Cardiomyopathy
Conduction
Connexin43
Desmocollin-2
Desmoglein-2
Desmosome
Functional studies
Gap junction
Mutation
Plakoglobin

Abbreviations

ARVC
arrhythmogenic right ventricular cardiomyopathy
Cx43
connexin43
DAPI
4′,6-diamidino-2-phenylindole
DSC2
desmocollin-2
DSG2
desmoglein-2
DSP
desmoplakin
GFP
green fluorescent protein
GST
glutathione-S-transferase
ICS
intracellular cadherin segment
PG
plakoglobin
PKP2
plakophilin-2
RV
right ventricle
YFP
yellow fluorescent protein

Cited by (0)

This work was supported by British Heart Foundation Programme Grant RG/04/010 to Drs. Gehmlich, Syrris, and McKenna and Project Grant PG/05/112 to Dr. Lambiase; the Heart Rhythm Society to Dr. Asimaki; and National Institutes of Health Grant HL102361 to Dr. Saffitz. 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. Dr. Gehmlich's present address is Department of Cardiovascular Medicine, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom.