Abstract
In this issue, guest editors Kathy Green and Mario Delmar, who are leaders in the fields of epidermal desmosomes and heart intercalated discs respectively, have joined forces to collate a two-part series of reviews focused on junctional proteins and genes that are targets of skin and heart diseases.
Desmosomes mediate strong intercellular adhesion and are sites of cytoskeletal attachment for intermediate filaments. The desmosome-intermediate filament network forms a supracellular web that braces the cell against external abrasive and internal contractile forces. Although present in all epithelia, desmosomes are found in great abundance within heavily stressed tissues such as epidermis and heart. Cell junctions were studied extensively by electron microscopy in the mid-1900s. Beautiful electron micrographs taken by Doug Kelly, Don Faucett, McNutt and Weinstein. Jane Overton and Marilyn Faquhar, have been immortalized in textbooks. In 1974, Christine Skerrow and Gideon Matoltsy isolated desmosomes from the pellet left behind after citric acid solubilization of cow snout epidermal keratins. Their work paved the way for the isolation of desmosomal proteins and their use as the antigenic source for the production of antibodies in the early 80s by the laboratories of Cowin and Garrod, Werner Franke, Malcolm Steinberg, and Kathleen Green. The similarity between desmosomal patterns of immunofluorescence and those generated by sera from patients with the autoimmune blistering disease of the skin, pemphigus, became immediately apparent. These antibodies pointed to the relationship between epithelial desmosomes and heart intercalated discs, showing that some plaque components, for example, PG and DP1, were highly conserved, whereas desmosomal cadherins showed tissue specificity. They also facilitated the cloning of desmosomal cDNAs. The subsequent identification of human desmosomal genes in the early 1990s paved the way to link defects in desmosomal components with further human diseases.
In this issue, Sen Chowdhry and McKenna present the history of the discovery of mutations in plakoglobin and desmoplakin that result in cardiac arrhythmia and cutaneous pathologies found in Naxos and Carvajal syndromes. Azimaki and Saffitz review how failure to localize these plaque components to intercalated discs is a hallmark of much more frequent arrhythmogenic cardiomyopathies associated with sudden cardiac death. Mechthild Hatzfeld presents a comprehensive review of the plakophilins, which perhaps make the largest contribution to heart disease and skin fragility. An important point to emerge from the use of antibodies was the concept that the intercalated disc is in fact a composite junction composed of mixtures of desmosomal, adherens junction, and gap junctions. Zhang and Shaw present a review suggesting that trafficking of connexins to these composite sites may contribute to some form of cardiac disease. Barika and Garrod and Spindler and Waschke review desmosomal adhesion mechanisms, focusing on the role of post-translational modification in modulating desmosomal hyperadhesion, and its contribution towards skin pathologies such as pemphigus. Peter Koch and colleagues review the role transcriptional regulation of desmosomal components by p63 in the skin fragility syndrome Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome.