Plectin is a widely expressed cytomatrix component involved in the attachment of 
the cytoskeleton to the plasma membrane. We have recently reported that the skin 
and muscles of three patients affected by epidermolysis bullosa simplex with 
muscular dystrophy (MD-EBS), a genetic disorder characterized by skin blistering 
associated with muscle involvement, are not reactive with antibodies specific to 
plectin. We demonstrated that in the skin, lack of plectin leads to failure of 
keratin filaments to connect to the plasma membrane via the hemidesmosomes, 
whereas in the muscle the deficient expression of the molecule correlates with 
an aberrant localization of desmin in the muscle fibers. In this study we 
demonstrate that in a MD-EBS kindred with two affected members, the disease 
results from a homozygous nonsense mutation in the plectin (PLEC1) gene leading 
to a premature stop codon (CGA to TGA) and decay of the aberrant plectin 
messenger RNA. The segregation of the mutated allele implicates the mutation in 
the pathology of the disorder. These results confirm the critical role of 
plectin in providing cell resistance to mechanical stresses both in the skin and 
the muscle.