On the basis of findings of a lethal defect in cardiac morphogenesis at embryonic day 10.75 in mice homozygous with respect to a deletion mutation of Pkp2 (Grossmann et al., 2004), Gerull et al. (2004) hypothesized that mutations ... On the basis of findings of a lethal defect in cardiac morphogenesis at embryonic day 10.75 in mice homozygous with respect to a deletion mutation of Pkp2 (Grossmann et al., 2004), Gerull et al. (2004) hypothesized that mutations in human PKP2 may account for ARVC. They collected samples from a total of 120 unrelated ARVC probands of Western European descent (101 males and 19 females) who were diagnosed using criteria proposed by McKenna et al. (1994). Gerull et al. (2004) sequenced all 14 PKP exons, including flanking intronic splice sequences, and identified 25 different heterozygous mutations in 32 probands (27 males and 5 females). Gerull et al. (2004) stated that inasmuch as mutations causing ARVC have been identified in PKP2, JUP (encoding plakoglobin: 173325), and DSP (encoding desmoplakin; 125647), ARVC may be considered a disease of the desmosome. Desmosomes are complex multiprotein structures of the cell membrane and provide structural and functional integrity to adjacent cells (e.g., epithelial cells and cardiomyocytes). Desmosomal proteins also have a role in cell signaling. At least 3 groups of molecules contribute to the formation of desmosomes: desmosomal cadherins, armadillo-repeat proteins, and plakophilins. The plakophilins, which are armadillo-related proteins, contain 10 42-amino acid armadillo repeat motifs and are located in the outer dense plaque of desmosomes, linking desmosomal cadherins with desmoplakin and the intermediate filament system. Like other armadillo-repeat proteins, plakophilins are also found in the nucleus, where they may have a role in transcriptional regulation. Plakophilin-2 (PKP2; 602861) exists in 2 alternatively spliced isoforms (2a and 2b), interacts with multiple other cell adhesion proteins, and is the primary cardiac plakophilin (Mertens et al., 2001). Dalal et al. (2006) confirmed high prevalence of PKP2 mutations in a large cohort of patients with ARVD/C and reported that those with PKP2 mutations present with arrhythmia earlier than do patients with ARVD/C who do not have a PKP2 mutation.