Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex.

[epidermolysis bullosa simplex]

Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains . Mutations in the gene encoding plectin (PLEC 1 ) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB ): EB simplex with muscular dystrophy (EBS-MD ), and EB simplex with pyloric atresia (EBS-PA ). Here , we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin . We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients . In EBS-PA , expression of all plectin domains was found to be markedly attenuated or completely lost ; in EBS-MD , the expression of the N- and C-terminal domains of plectin remained detectable , although the expression of rod domains was absent or markedly reduced . Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD , and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype . These results also clearly account for the majority of EBS-MD PLEC 1 mutation restriction within the large exon 31 that encodes the plectin rod domain , whereas EBS-PA PLEC 1 mutations are generally outside exon 31 .