A MUTATION IN THE V1-END DOMAIN OF KERATIN-1 IN NON-EPIDERMOLYTIC PALMAR-PLANTAR KERATODERMA

Mutations in keratin 9 have been found in families with an epidermolyt ic form of palmar-plantar keratoderma (PPK). In another form of PPK (U nna-Thost type), epidermolysis is not observed histologically. We stud ied a pedigree with this non-epidermolytic form of PPK. By gene linkag e analysis, the type I keratin locus could be excluded but complete li nkage with the type II keratin region was found. Sequence analysis ide ntified a single base change in the amino-terminal V1 variable subdoma in of keratin 1, which caused a lysine to isoleucine substitution. Thi s non-conservative mutation completely cosegregated with the disease a nd was not observed in 50 unrelated unaffected individuals. An examina tion of keratin amino-terminal sequences revealed a previously unrepor ted 22-residue window in the Vi subdomain that is conserved among most type II keratins. The altered lysine is an invariant residue in this conserved sequence. Previously described keratin mutations affect the central regions important for filament assembly and stability, and cau se diseases characterized by cellular degeneration or disruption. This is the first disease mutation in a keratin chain variable end region. The observation that it is not associated with epidermolysis supports the concept that the amino-terminal domain of keratins may be involve d in supramolecular interactions of keratin filaments rather than stab ility. Therefore, hyperkeratosis associated with this mutation may be due to perturbations in the interactions of the keratin end domain wit h other cellular components.