Role of Plakins in Human Genetic Disease

The mammalian plakins comprise a small family of seven large proteins: bullous pemphigoid antigen 1, desmoplakin, envoplakin, epiplakin, microtubule-actin crosslinking factor 1, periplakin and plectin. Their main functions consist of organising the different components of the cytoskeleton, crosslinking them to each other and anchoring them to various cell–matrix and cell–cell adhesion complexes. Thereby, these cytolinkers regulate cell stiffness, adhesion, migration and polarisation in a dynamic way. They can also interact with signal transducers, serve as scaffolds for signalling complexes and modulate vesicle trafficking. Congenital or engineered mutations in human and mouse plakin genes, respectively, reveal their essential functions in tissues either subjected to mechanical stress, such as the skin, skeletal and cardiac muscle, or highly sensitive to cytoskeletal and vesicle transport disorganisation, the nervous system. The pleiotropic diseases caused by plakin mutations reflect their multiple functions that have not yet been fully elucidated. Key Concepts The plakins are a family of cytolinker proteins that connect the three components of the cytoskeleton, intermediate filaments (IFs), microfilaments and microtubules (MTs), to each other and to junctional complexes at the cell membrane. The plakin family can be subdivided into three classes: (1) the canonical IF-anchoring plakins: BPAG1e, desmoplakin, envoplakin, periplakin and plectin, (2) the atypical IF-interacting plakin: epiplakin and (3) the MT-binding spectraplakins: BPAG1a/b and MACF1a/b. The plakins often have a dynamic function on the cytoskeleton organisation, can modulate cell signalling and serve as scaffolds for signal transducers. The plakins also play a role in the positioning and function of organelles and regulate vesicular trafficking. Mutations in plakin genes can cause pleiotropic diseases, such as skin blistering, muscular dystrophy, cardiomyopathy and autonomic neuropathy. Despite the delimitation of plakin subdomains and the present knowledge of plakin functions, there is no obvious genotype–phenotype relationship. Keywords: plakin; spectraplakin; cytolinker; hemidesmosome; desmosome; cytoskeleton; intermediate filaments; cell adhesion; cell migration