The cytoskeleton of epithelial cells is formed by heteropolymeric
keratin proteins characterized by a central alpha-helical rod flanked by nonhelical head and tail domains of variable sequence. Most mutations described in 18 distinct
keratins disrupt highly conserved regions at the boundaries of the rod, which have been recognized as zones of overlap during
keratin alignment and assembly into intermediate filaments. We recently reported the first mutation located in a
keratin tail domain (V2) in
ichthyosis hystrix Curth-Macklin. In this study, we report two novel frameshift mutations that are predicted to alter the tail of
keratin 1 or
keratin 5, leading to an atypical form of
epidermolytic hyperkeratosis and a mild form of
epidermolysis bullosa simplex, respectively. Mutation analysis of the patient with
epidermolytic hyperkeratosis revealed a de novo heterozygous
nucleotide insertion (1752insG) in exon 9 of KRT1, predicted to result in an aberrant 69 residue
keratin 1 tail. In the patient with mild
epidermolysis bullosa simplex, we identified a single
nucleotide deletion (1635delG) in exon 9 of KRT5 leading to frameshift and translation of an abnormal V2 domain, 35
amino acids longer than the native
keratin 5 tail. Our results, together with previous observations, establish the existence of a subgroup of
keratin disorders due to frameshift mutations altering the
keratin tail domains that are characterized by phenotypic heterogeneity.