Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease) Original Research Article

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded. This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin. Methods We studied 19 individuals with Naxos disease, as well as unaffected family members and unrelated individuals from the neighbouring Greek islands of Naxos and Milos. Gene sequence was determined by reverse transcriptase PCR from RNA isolated from the skin of an affected individual and mutations in other cases were confirmed by restriction-enzyme analysis. Findings A homozygous 2 base pair deletion in the plakoglobin gene was identified only in the 19 affected individuals. This deletion caused a frameshift and premature termination of the protein, which was shown by western blot analysis. 29 clinically unaffected family members were heterozygous for the mutation; 20 unrelated individuals from Naxos and 43 autosomal dominant ARVC probands were homozygous for the normal allele. Interpretation The finding of a deletion in plakoglobin in ARVC suggests that the proteins involved in cell-cell adhesion play an important part in maintaining myocyte integrity, and when junctions are disrupted, cell death, and fibrofatty replacement occur. Therefore, the discovery of a mutation in a protein with functions in maintaining cell junction integrity has important implications for other dominant forms of ARVC, related cardiomyopathies, and other cutaneous diseases.