Mutations in genes encoding desmosomal proteins have been implicated in the 
pathogenesis of heart and skin diseases. This has led to the hypothesis that 
defective cell-cell adhesion is the underlying cause of injury in tissues that 
repeatedly bear high mechanical loads. In this study, we examined the effects of 
two different mutations in plakoglobin on cell migration, stiffness, and 
adhesion. One is a C-terminal mutation causing Naxos disease, a recessive 
syndrome of arrhythmogenic right ventricular cardiomyopathy (ARVC) and abnormal 
skin and hair. The other is an N-terminal mutation causing dominant inheritance 
of ARVC without cutaneous abnormalities. To assess the effects of plakoglobin 
mutations on a broad range of cell mechanical behavior, we characterized a model 
system consisting of stably transfected HEK cells which are particularly well 
suited for analyses of cell migration and adhesion. Both mutations increased the 
speed of wound healing which appeared to be related to increased cell motility 
rather than increased cell proliferation. However, the C-terminal mutation led 
to dramatically decreased cell-cell adhesion, whereas the N-terminal mutation 
caused a decrease in cell stiffness. These results indicate that different 
mutations in plakoglobin have markedly disparate effects on cell mechanical 
behavior, suggesting complex biomechanical roles for this protein.