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.