Plectin-related skin diseases

The Structure of the Plakin Domain of Plectin Reveals an Extended Rod-like Shape

“…Plakins are a family of very large proteins that interconnect and organize the intermediate filaments (IF), 4 microtubules, and microfilaments of the cytoskeleton and tether them to membrane-associated structures (1,2). So far, seven plakins have been described in mammals; these are plectin, bullous pemphigoid antigen 1 (BPAG1), desmoplakin, microtubule and actin cross-linking factor 1 (MACF1, also known as ACF7), envoplakin, periplakin, and epiplakin.…”

“…Plectin also connects IFs to organelles such as the nucleus and mitochondria (3). Defects in the PLEC gene cause various forms of the blistering disease epidermolysis bullosa simplex (EBS), which may occur only with skin fragility, as found in EBS Ogna type, or may be associated with muscular dystrophy or pyloric atresia (4). These diseases highlight the important role of plectin in the homeostasis of tissues subjected to mechanical stress, such as skin and muscle.…”

Epidermolysis bullosa simplex in sibling Eurasier dogs is caused by a PLEC non‐sense variant

“…The protein comprises four major domains: the amino-terminal or calponin homology domain, the plakin domain, the rod domain and the carboxy terminal domain; [4][5][6]8,12 the different isoforms (i.e. 1a-g) correlate with tissue specificity (e.g.…”

“…1a and c for epidermis; 1d for skeletal muscle). [4][5][6] Plectin 1a is the only isoform known to bind to the beta unit of the integrin α6;24 via the plakin domain, adjacent to the amino terminus, and to keratin intermediate filaments via its carboxy terminal domain. Therefore, plectin serves as a vital structural component of the BMZ; as a bridge between the inner cytoskeleton to the basal lamina.…”

“…12 Like the Eurasier puppies, the severe EBS-PA phenotype may result from plectin variants that affect the rod and carboxy domain and thereby impair binding to keratin and possibly to integrin β4 as an alternative binding site. 4,5 In the affected dogs, the hemidesmosomes were abnormally electron dense and globular to ovoid with thickening of the connecting tonofilaments. The thickening of keratin may represent a compensatory change due to the truncated protein and failure to cross-link.…”