Abstract 1054: Severe Manifestation of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a Family with a Nonsense-Mutation in the Plakophilin-2 Gene
Mutations in desmosomal proteins, including plakophilin-2 (PKP2), have been identified recently as major causes of ARVC. We identified a large family with an inherited form of ARVC due to a nonsense-mutation in the PKP2 gene (C1237T, R413X). Members of this family display a severe ARVC phenotype with frequent occurence of sudden cardiac death (SCD) at young age (5 cases at age 14 to 29) occuring mostly during physical activity. Compared to published data, SCD occurred at significantly younger age in this family (mean age at SCD 33.4 vs. 21 years, p = 0,0005). The age at onset of arrhythmia in the family members was significantly lower compared to patients with ARVC due to other PKP2 mutations (data from literature, 24.8 vs. 32.5 years, p = 0.0139). The penetrance of ARVC is strongly gender dependent (all sequenced male but only 30% of female carriers developed the disease). ECGs of affected family members show T-wave inversions in the precordial leads from V1 to V4 or V5 indicating severe RV involvement. Left ventricular (LV) myocardial biopsies showed pathological nuclei, hypertrophied cardiomyocytes and reduced myofibers as well as fibrosis indicating LV involvement. Electron microscopy revealed abnormal mitochondria and dilated intercalated discs. mRNA expression analysis as well as sequencing points to the transcription of the defect allele leading presumably to a truncated protein, missing 8 of the 10 carboxyterminal armadillo repeats. A mouse model overexpressing the R413X PKP2 has also been established and will allow a detailed analysis of underlying mechanisms, including possible defects in desmosomal architecture, wnt signalling and PKP2 nuclear function.