Novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds

We report a novel mutation in the exon 6 splice donor site of keratin 1 (G4134A) that segregates with a palmoplantar keratoderma in three kindreds, The nucleotide substitution leads Co the utilization of a novel in-frame splice site 54 bases downstream of the mutation with the subsequent insertion of 18 amino acids into the 2B rod domain. This mutation appears to have a milder effect than previously described mutations in the helix initiation and termination sequence on the function of the rod domain, with regard to filament assembly and stability. Affected individuals displayed only mild focal epidermolysis in the spinous layer of palmoplantar epidermis, in comparison with cases of bullous congenital ichthyosiform erythroderma also due to keratin 1 mutations, which show widespread and severe epidermolysis. This study describes a novel mutation in KRT1 that results in a phenotype distinct from classical bullous congenital ichthyosiform erythroderma.