Muscle-Related Plectinopathies

Abstract

Plectin is a giant cytoskeletal crosslinker and intermediate filament stabilizing protein. Mutations in the human plectin gene (PLEC) cause several rare diseases that are grouped under the term plectinopathies. The most common disorder is autosomal recessive disease epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), which is characterized by skin blistering and progressive muscle weakness. Besides EBS-MD, PLEC mutations lead to EBS with nail dystrophy, EBS-MD with a myasthenic syndrome, EBS with pyloric atresia, limb-girdle muscular dystrophy type R17, or EBS-Ogna. In this review, we focus on the clinical and pathological manifestations caused by PLEC mutations on skeletal and cardiac muscle. Skeletal muscle biopsies from EBS-MD patients and plectin-deficient mice revealed severe dystrophic features with variation in fiber size, degenerative myofibrillar changes, mitochondrial alterations, and pathological desmin-positive protein aggregates. Ultrastructurally, PLEC mutations lead to a disorganization of myofibrils and sarcomeres, Z- and I-band alterations, autophagic vacuoles and cytoplasmic bodies, and misplaced and degenerating mitochondria. We also summarize a variety of genetically manipulated mouse and cell models, which are either plectin-deficient or that specifically lack a skeletal muscle-expressed plectin isoform. These models are powerful tools to study functional and molecular consequences of PLEC defects and their downstream effects on the skeletal muscle organization.

Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control

“…However, subtle structural changes would not have been detected in these experiments and genetic mutations in the PLEC gene are associated with muscular dystrophy, characterized by the detachment of mitochondria from sarcoplasmic reticulum and mitochondrial clustering. 72 , 73 Moreover, assessment of the myofibrillar structure with SHG imaging and phalloidin labeling showed a loss of distinct longitudinal ridges and valleys in enzymatically dissociated fibers, and these fibers also had longer sarcomeres than mechanically dissected fibers (see Figures 1 A–1D). These results indicate that on isolation from their native microenvironment, the internal muscle fiber tension is reduced in enzymatically dissociated fibers, which might cause a rapid dedifferentiation of the adult muscle fiber phenotype.…”

fhl2bexpression ameliorates muscular dystrophy

“…Next, we asked whether Fhl2 upregulation in EOMs could be found across muscular dystrophies and therefore immunolabeled plecb -/- (Plectin) and obscnb -/- (Obscurin) mutant zebrafish EOMs (Fig. 2F), both resulting in muscular dystrophy when mutated in other models 37,38 . Interestingly, plecb -/- and obscnb -/- mutant zebrafish displayed increased numbers of Fhl2 positive myofibers compared to controls, similar to desma -/- ; desmb -/- EOMs (Fig.…”

“…Next, we asked whether Fhl2 upregulation in EOMs could be found across muscular dystrophies and therefore immunolabeled plecb -/-(Plectin) and obscnb -/-(Obscurin) mutant zebrafish EOMs (Fig. 2F), both resulting in muscular dystrophy when mutated in other models 37,38 .…”

Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease

“…Similarly, the gene PLEC (encoding the protein plectin) contains a missense variant in the coding region (ClinVar ID: 1043148, AAG > AAU) of its terminal exon and creates the PAS AAUAAA. This variant is associated with multiple diseases, such as muscular dystrophy, nail dystrophy, and skin disorders [39][40][41] . The expression of the de novo polyA site would generate the non-stop codon RNA isoform, which cannot produce the full-length protein (Fig.…”