Abstract 2291: Recapitulation of a Right Ventricular Phenotype in a Transgenic Mouse Model Overexpressing the Plakophilin-2 R413x Mutation That Causes Severe ARVC in a Large Family
Background: Mutations in desmosomal proteins, including plakophilin-2 (PKP2), have been identified recently as major causes of ARVC. Here we describe a large family (58 family members) with an inherited form of ARVC due to a nonsense-mutation in the PKP2 gene (c. 1237C>T, p. R413X).
Methods and Results: Linkage analysis of this family, including 10 affected and 10 unaffected family members, revealed a 2-point lod score of 4.51 (Θ=0) at the PKP-2 gene. Affected members of this family display a severe ARVC phenotype: sudden cardiac death (SCD), which occurs mostly during physical activity and at a significantly younger age in comparison to published data (median age at SCD 22 vs. 32 years, p<0.01; reference group from A. Tabib, Circulation 108, 2003). Besides this severe arrythmogenic phenotype the affected family members show classical signs of ARVC such as T-wave inversions, frequent PVCs on holter monitoring and fatty degeneration and wall motion abnormalities in cardiac MRI. Left ventricular (LV) myocardial biopsies showed pathological nuclei, hypertrophied cardiomyocytes and fibrosis indicating LV involvement. The penetrance of this mutation is strongly gender dependent (100% of male but only 30% of confirmed female mutation carriers developed the disease, p<0.05). mRNA expression analysis followed by sequencing points to the transcription of the mutant allele leading presumably to a truncated protein, missing 8 of the 10 carboxyterminal armadillo repeats. Concordant with the gender-dependent penetrance in patients, male, but not female transgenic mice with heart-directed alpha-MHC promotor driven overexpression of the mutant R413X PKP2 protein (PKP2-Tg), showed increased right ventricular size at 12 months of age. Moreover, ventricular action potential durations were slightly shortened in isolated, beating PKP2-Tg hearts (APD90 PKP2-Tg 30±2, APD90 WT 38±3 at a paced cycle length of 120 ms, p<0.05).
Conclusion: The R413X-PKP2 mutation causes a severe form of ARVC. A morphological and electrophysiological phenotype is recapitulated in a mouse model overexpressing the mutation suggesting a role for the truncated protein in the pathophysiology of the disease. This model might help to unravel the underlying molecular mechanisms.