Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy

In a distinct autosomal recessive variant of epidermolysis bullosa, EB- MD,life-long skin blistering is associated with late-onset muscular dystrophyof unknown etiology. Electron microscopy of these patients' skin suggeststhat tissue separation occurs intracellularly at the level of thehemidesmosomal inner plaque, which contains plectin, a high molecularweight cytoskeletal associated protein, also expressed in the sarcolemma ofthe muscle. In this study, we report two patients with EB-MD, each with ahomozygous deletion mutation in the plectin gene, PLEC1. In the first case,the proband and her similarly affected sister had a homozygous 9 bpdeletion mutation, designated as 2719de19, which resulted in elimination ofthree amino acids, QEA, in a sequence of 23 amino acids entirely conservedbetween the mouse and human sequences. The proband in the second familydemonstrated a single nucleotide deletion at position 5866, designated as5866delC, which resulted in frameshift and a premature termination codonfor translation 16 bp downstream from the site of deletion. The absence ofplectin in the hemidesmosomes, as reflected by negative immunofluorescencewith an anti-plectin antibody (HD-1), associated with fragility of basalkeratinocytes, implicates plectin as critical for binding of intermediatekeratin filament network to hemidesmosomal complexes. The function ofplectin as a putative attachment protein also in the muscle would explainthe clinical phenotype consisting of cutaneous fragility and musculardystrophy in EB-MD.