Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy

Mutations of the human plectin gene (Plecl) cause amosomal recessive epidemiolysis bullosa simplex with Muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic Muscle alterations ill EBS-MD. Analysis of a 25-yr old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins 16/ 13803ins 16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting,, that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD. our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations Such as desminopathies or alpha-B-crystallinopathies.