The effect of plakophilin-2 gene mutations on the activity of canonical WNT signaling

Resumo

Plakophilin-2 is a desmosomal protein encoded by PKP2 gene. Desmosomal proteins are usually considered as structural proteins with the main function of maintaining intercellular interactions. Genetic studies revealed that mutations in desmosomal genes could lead to arrhythmogenic right ventricular cardiomyopathy, a heart disease characterized by substitution of cardiomyocytes by adipose and fibrotic tissue predominantly in the right ventricle. Wnt signaling is a signal transduction pathway presumably involved in the development of pathology. The purpose of this study was to investigate Wnt activity in cells with wild-type and mutant PKP2 gene during adipogenic and cardiomyogenic differentiation. We used multipotent mesenchymal stromal cells and iPS cells generated from a patient carrying PKP2 gene mutation. We found that cells with mutant PKP2 exhibited lower transcriptional activity of β-catenin, a key player of Wnt signaling, as well as attenuated expression of its targets SOX2 and SOX9. These findings suggest a signaling role of plakophilin2 by regulating Wnt activity