EPIDERMOLYSIS-BULLOSA SIMPLEX - A KERATIN-5 MUTATION IS A FULLY DOMINANT ALLELE IN EPIDERMAL CYTOSKELETON FUNCTION

To explore the relationship between abnormal keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and b listering, we sought to determine the functional consequences of homoz ygosity for a dominant keratin defect. We describe a family with an au tosomal dominant skin-blistering disorder, epidermolysis bullosa simpl ex, Koebner subtype (EBS-K), that has a novel point mutation, occurrin g in the keratin 5 gene (KRT5), that predicts the substitution of an e volutionarily conserved lysine by an asparagine residue (K173N). Unlik e previous heterozygous mutations located within the initial segment o f domain 1A of keratin molecules, K173N heterozygosity did not result in severe disease or clumping of keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it h em each of her affected first-cousin parents. Despite a lack of normal keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the keratin IF cytoskeleton of the ho mozygous individual. These data demonstrate that the K173N mutation be haves as a fully dominant allele and indicate that a limited number of abnormal keratin molecules are sufficient to impair cytoskeletal func tion and elicit epidermal fragility and blistering.