Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Molecular characterization of disease mechanisms involved in arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disorder that predominantly affects the right ventricle, and is associated with ventricular tachycardia and sudden death.

ARVC is mainly caused by mutations in genes encoding desmosomal proteins. We have described mutations in plakophilin-2 (PKP2) and desmocollin-2 (DSC2) as a cause of autosomal dominant ARVC for the first time (Fig.). PKP2 mutations account for a significant proportion of ARVC cases (10-45%). PKP2 and DSC2 are components of the desmosomal intercellular junction complex known to be essential for maintaining tissue integrity and increasingly implicated in cell signaling.

The involvement of multiple desmosomal proteins has led to speculation regarding the sensitivity of myocardium to mechanical disruption (cell adhesion defect). Alternatively, recent data suggest alterations in the canonical Wnt/β-catenin signaling. However the pathogenic mechanisms leading to ARVC are widely unknown.  The goal of our work will be to further understand which mechanisms are involved in the pathogenesis of ARVC and, eventually, to target therapy towards defects in specific pathways.

Towards this goal we will investigate the biological effects of ARVC causing mutations in various cell culture systems and we will generate several transgenic mouse models with targeted disruption and induced overexpression of desmosomal proteins. These models will be characterized in vivo and in vitro and the contribution of canonical Wnt/β-catenin signaling and/or potential alternative pathways in the pathogenesis of the disease will be analyzed. We hypothesize that ARVC causing mutations have common downstream effects on various disease programs and influence cardiac remodeling processes including adipogenesis and fibrosis.

In addition we will focus on human genetics of ARVC and determine which clinical and/or genetic risk factors may influence the genesis of ARVC. We are also interested in the elucidation of the reduced penetrance and variability of the disease in family based studies. In the future, an improved understanding of the pathogenesis of ARVC will provide new diagnostic and prognostic markers and, eventually, new therapeutic targets in humans.

Mutant Desmocollin-2 (DSC2) causes ARVC. (A) Partial nucleotide sequence of DSC2 intron 5 -exon 6 junction. The genomic sequence of the affected patient shows a heterozygous A>G transition in the splice acceptor site position of intron 5. (B) Western blot analysis of a right ventricular biopsy sample obtained from the patient with the DSC2 mutation c.631-2A>G. Note that the amount of DSC2 in the patient is reduced when compared to control myocardium. (C) Allele specific quantitative real-time PCR of DSC2 wildtype (WT) and mutant (MUT) mRNA of cardiac tissue derived from patient sample (P) and control samples (C). Note the reduced expression of the mutant allele in cardiac tissue in the patient. (D) and (E) Knockdown of dsc2 in zebrafish. High-resolution pictures of the heart of morphant embryo (E) compared to control embryo (D) at 48 hpf injected morpholino dsc2-1. (F) and (G) Transmission electron microscopy of cardiac desmosomes from a control embryo (F) and morphant embryo (G) at 48 hpf. Note the loss of the extracellular electron-dense midline in desmosomes of morphant embryos. a: atrium; v: ventricle; (Figure reproduced from The American Journal of Human Genetics 79:1081-1088, 2006. Copyright © 2006 by The University of Chicago Press. All rights reserved.)

Project Related Publications

Heuser A, Plovie ER, Ellinor PT, Grossmann, KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B. (2006). Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy (ARVC). Am J Hum Genet. Dec;79 (6):1081-8.

Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, Macrae CA, Peters S, Grossmann KS, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L.(2004). Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. [Corrigendum in: Nat Genet. 2005 Jan;37(1):106]. Nat. Genet. 36, 1162-1164.

Involved Scientists

Arnd Heuser (Postdoc)

Robert Zinke (PhD-student)

Florian Kirchner (PhD-student)

Brenda Gerull (Postdoc, responsible for medical attendence)