The many faces of plectin and plectinopathies: pathology and mechanisms.

Plectin, a giant multifunctional cytolinker protein, plays a crucial role in stabilizing and orchestrating intermediate filament networks in cells. Mutations in the human plectin gene result in multiple diseases manifesting with muscular dystrophy, skin blistering, and signs of neuropathy. The most common disease caused by plectin deficiency is epidermolysis bullosa simplex (EBS)-MD, a rare autosomal-recessive skin blistering disorder with late-onset muscular dystrophy. EBS-MD patients and plectin-deficient mice display pathologic desmin-positive protein aggregates, degenerated myofibrils, and mitochondrial abnormalities, the hallmarks of myofibrillar myopathies. In addition to EBS-MD, plectin mutations have been shown to cause EBS-MD with a myasthenic syndrome, limb-girdle muscular dystrophy type 2Q, EBS with pyloric atresia, and EBS-Ogna. This review focuses on clinical and pathological manifestations of these plectinopathies. It addresses especially plectin's role in skeletal muscle, where a loss of muscle fiber integrity and profound changes of myofiber cytoarchitecture are observed in its absence. Furthermore, the highly complex genetic and molecular structure of plectin is discussed; a high number of differentially spliced exons give rise to a variety of different isoforms, which fulfill distinct functions in different cell types and tissues. Plectin's abilities to act as a dynamic organizer of intermediate filament networks and to interact with a multitude of different interaction partners are the basis for its function as a scaffolding platform for proteins involved in signaling. Finally, the article addresses a series of genetically manipulated mouse lines that were generated to serve as powerful models to study functional and molecular consequences of plectin gene defects.