PKP2

PKP2 encodes plakophilin-2, a desmosomal protein that contributes to cell–cell adhesion in epithelial and cardiac tissues. The protein is a component of the desmosome plaque, helping to link cadherin-based adhesion molecules to intermediate filaments. Plakophilin-2 contains armadillo-repeat domains and participates in desmosome assembly and stabilization, supporting mechanical coupling between neighboring cells, particularly in tissues that experience constant mechanical stress such as the heart.

PKP2 is highly expressed in the heart, especially at the intercalated discs that connect cardiomyocytes. In conjunction with other desmosomal proteins such as desmoplakin (DSP), desmocollin-2 (DSC2), and desmoglein-2 (DSG2), plakophilin-2 helps coordinate adhesion and signaling. Beyond structural roles, PKP2 influences signaling pathways related to cell fate and tissue organization, including interactions that affect Wnt/β-catenin signaling in some contexts.

Pathogenic variants in PKP2 are a major cause of arrhythmogenic right ventricular cardiomyopathy (ARVC), designated ARVC type 5 when tied to PKP2 mutations. Inherited in an autosomal dominant pattern, PKP2-related ARVC shows incomplete penetrance and variable expressivity. The disease phenotype typically features fibrofatty replacement of myocardium, arrhythmias, and an increased risk of sudden cardiac death, with some patients exhibiting left ventricular involvement as the disease progresses.

Diagnosis often involves genetic testing for PKP2 variants in individuals with suspected ARVC, supported by imaging and electrocardiographic findings. Management centers on reducing arrhythmic risk and may include activity modification, antiarrhythmic therapy, beta-blockers, and implantable cardioverter-defibrillators for high-risk patients. In advanced cases, heart transplantation may be considered. Ongoing research seeks to clarify genotype–phenotype correlations and the precise mechanisms by which PKP2 mutations disrupt desmosomal function.