AN ALANINE TO PROLINE MUTATION IN THE 1A ROD DOMAIN OF THE KERATIN-10CHAIN IN EPIDERMOLYTIC HYPERKERATOSIS

We report a mutation in a case of epidermolytic hyperkeratosis that re sults in a proline for alanine substitution in the residue position 12 of the 1A subdomain of the keratin 10 chain (codon 158). The disease phenotype is consistent with the inappropriate substitution of a proli ne near the beginning of the rod domain, because it is likely to serio usly disrupt the structural organization of coiled-coil molecules with in keratin intermediate filaments. Mutations/substitutions in this pos ition have not been reported in any keratin disease. Position 12 is an alanine in all intermediate filament chains, and lies in the outer It heptad position of the coiled-coil. In vitro peptide interference ass embly assays revealed that substitutions that alter residue size or ch arge at this position primarily interfere with keratin filament elonga tion.