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

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an aut osomal 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 islan ds of Naxos and Miles. Gene sequence was determined by reverse transcriptas e PCR from RNA isolated from the skin of an affected individual and mutatio ns in other cases were confirmed by restriction-enzyme analysis. Findings A homozygous 2 base pair deletion in the plakoglobin gene was iden tified only in the 19 affected individuals. This deletion caused a frameshi ft and premature termination of the protein, which was shown by western blo t analysis. 29 clinically unaffected family members were heterozygous for t he 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 th at the proteins involved in, cell-cell adhesion play an important part in m aintaining myocyte integrity, acid 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 impo rtant implications for other dominant forms of ARVC, related cardiomyopathi es, and other cutaneous diseases.