Rationale Arrhythmogenic cardiomyopathy (ACM) is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (plakoglobin) mutations are responsible for a subset of ACM patients that exhibit cardiac arrhythmias and dysfunction, palmo-planter keratosis, and hair abnormalities (cardiocutaneous syndromes). Objective To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. Methods and Results Expression of chondroitin sulfate proteoglycan 4 (CSPG4) was detected in epidermal keratinocytes and the cardiac conduction system (CCS). CSPG4pos cells constituted ~ 5.6±3.3% of the non-myocyte cells in the mouse heart. Inducible post-natal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibro-adipocytes, as in human ACM. The mice exhibited palmo-plantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. Conclusions Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in ACM patients and cardiocutaneous syndromes.