BACKGROUND: -Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder mainly caused by dominant mutations in several components of the cardiac desmosome including plakophilin-2 (PKP2) - the most prevalent disease gene. Little is known about the underlying genetic and molecular mechanisms of missense mutations located in the armadillo (ARM) domains of PKP2 as well as their consequences on human cardiac pathology. METHODS AND RESULTS: -We focused on in vivo and in vitro studies of the PKP2 founder mutation c.2386T>C (p.C796R) and demonstrated in cardiac tissue from two related mutation carriers a patchy expression pattern ranging from unchanged to totally absent immunoreactive signals of PKP2 and other desmosomal proteins. In vitro expression analysis of mutant PKP2 in cardiac derived HL-1 cells revealed unstable proteins which fail to interact with desmoplakin and are targeted by degradation involving calpain proteases. Bacterial expression, crystallization and structural modeling of mutated proteins impacting different ARM domains and helices of PKP2 confirmed their instability and degradation, resulting in the same remaining protein fragment which was crystallized and used to model the entire ARM domain of PKP2. CONCLUSIONS: -The p.C796R and other ARVC-related PKP2 mutations indicate loss of function effects by intrinsic instability and calpain proteases mediated degradation in in vitro model systems suggesting haploinsufficiency as the most likely cause for the genesis of dominant ARVC due to mutations in PKP2.
Molecular Insights into Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Plakophilin-2 Missense Mutations.,Kirchner F, Schuetz A, Boldt LH, Martens K, Dittmar G, Haverkamp W, Thierfelder L, Heinemann U, Gerull B Circ Cardiovasc Genet. 2012 Jul 9. PMID:22781308
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↑ Kirchner F, Schuetz A, Boldt LH, Martens K, Dittmar G, Haverkamp W, Thierfelder L, Heinemann U, Gerull B. Molecular Insights into Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Plakophilin-2 Missense Mutations. Circ Cardiovasc Genet. 2012 Jul 9. PMID:22781308 doi:10.1161/CIRCGENETICS.111.961854