Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy

Background Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiac disorder characterized by life-threatening ventricular arrhythmias and fibrofatty replacement of myocardial tissue. Recent data suggest a dominant mode of inheritance in ARVD due to mutations in desmosomal proteins, plakophilin-2 (PKP2) in particular. We carried out a search for PKP2 mutations in the Finnish population representing a genetic isolate. Methods Mutations were detected by direct sequencing of PKP2 exons in 29 unrelated ARVD patients. Subcellular changes in ARVD associated with PKP2 mutations were searched for using immunohistochemistry and electron microscopy. Results We identified three PKP2 amino acid substitutions, absent in controls, in three (10%) cases. Two of them (Q62K and N613K) co-occurred in a patient with arrhythmia and structural changes of the heart. Visualized with plakophilin-2 antibodies, the intercalated disks in this compound heterozygous ARVD sample appeared wavier than in non-ARVD controls. Partial irregularities were occasionally seen in the organization and distribution of the cell-cell junctions. Relatives carrying one of these mutant alleles were phenotypically normal or showed only limited electrocardiographic (ECG) changes. The third substitution (Q59L) was detected in two ARVD probands with ventricular tachycardias, ECG abnormalities and right ventricular structural alterations. Conclusions We identified two novel plakophilin-2 missense mutations associated with 10% of ARVD, and a previously reported Q62K variant with a possible disease modifying role. The low prevalence of predominantly missense mutations may present population-specific differences in the pathogenesis of ARVD. Our preliminary data also suggest that ultrastructural cell junction abnormalities may associate with plakophilin-2 mutations.