Plectin defects in epidermolysis bullosa simplex with muscular dystrophy

Epidermolysis bullosa simplex with muscular dystrophy (EBS‐MD, MIM 226670) is caused by plectin defects. We performed mutational analysis and immunohistochemistry using EBS‐MD (n = 3 cases) and control skeletal muscle to determine pathogenesis. Mutational analysis revealed a novel homozygous plectin‐exon32 rod domain mutation (R2465X). All plectin/HD1‐121 antibodies stained the control skeletal muscle membrane. However, plectin antibodies stained the cytoplasm of type II control muscle fibers (as confirmed by ATPase staining), whereas HD1‐121 stained the cytoplasm of type I fibers. EBS‐MD samples lacked membrane (n = 3) but retained cytoplasmic HD1‐121 (n = 1) and plectin staining in type II fibers (n = 3). Ultrastructurally, EBS‐MD demonstrated widening and vacuolization adjacent to the membrane and disorganization of Z‐lines (n = 2 of 3) compared to controls (n = 5). Control muscle immunogold labeling colocalized plectin and desmin to filamentous bridges between Z‐lines and the membrane that were disrupted in EBS‐MD muscle. We conclude that fiber‐specific plectin expression is associated with the desmin‐cytoskeleton, Z‐lines, and crucially myocyte membrane linkage, analogous to hemidesmosomes in skin. Muscle Nerve, 2006