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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The most frequent ARVC genes encode desmosomal proteins of which mutations in desmoglein-2 (DSG2), account for 10%-20% of cases. This study aimed to investigate howDSG2mutations contribute to the pathogenesis of ARVC. Initial mutation analysis ofDSG2in 71 probands identified the first family reported with recessively inherited ARVC due to a missense mutation. In addition, three recognizedDSG2mutations were identified in 12 families. These results and further mutation analyses of four additional desmosomal genes indicated that ARVC caused byDSG2mutations is often transmitted by recessive or digenic inheritance. Because desmosomal proteins are also expressed in skin tissue, keratinocytes served as a cell model to investigate DSG2 protein expression by Western blotting, 2D-PAGE, and liquid chromatography-mass spectrometry. The results showed that heterozygous mutation carriers expressed both mutated and wild-type DSG2 proteins. These findings were consistent with the results obtained by immunohistochemistry of endomyocardial biopsies and epidermal tissue of mutation carriers, which indicated a normal cellular distribution of DSG2. The results suggested a dominantnegative effect of themutated DSG2 proteins because they were incorporated into the desmosomes.