PLEC encodes plectin, a giant cytoskeletal crosslinker protein that interlinks intermediate filaments with microtubules and microfilaments while anchoring intermediate filaments to desmosomes and hemidesmosomes 1. In muscle tissue, plectin serves as a structural component critical for myofiber integrity, with isoform 9 playing a major role in maintaining muscle organization 1. PLEC mutations cause plectinopathies, a group of rare diseases including epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), characterized by skin blistering and progressive muscle weakness with severe dystrophic muscle pathology 1. Skeletal muscle biopsies from EBS-MD patients reveal dystrophic features including myofibrillar disorganization, sarcomere disruption, and mitochondrial alterations 1. PLEC has also been implicated in congenital myasthenic syndromes affecting neuromuscular junction function 2. Beyond neuromuscular disease, PLEC expression is upregulated in heart failure and Alzheimer's disease, with PLEC variants colocalizing with both atrial fibrillation and Alzheimer's disease susceptibility loci 3. Additionally, PLEC participates in tumor progression pathways in breast cancer through NFκB1/CXCL9-mediated mechanisms 4, and variants affect structural brain connectivity 5.