Epidermolytic palmoplantar keratoderma is an autosomal dominant skin disorder characterized by hyperkeratosis of the palms and soles. Ultrastructurally the disease exhibits abnormal
keratin filament networks and tonofilament clumping like that found in the
keratin disorders of
epidermolysis bullosa simplex and
epidermolytic hyperkeratosis. The disease has been mapped to chromosome 17q11-q23 in the region of the
type 1 keratin gene locus and more recently mutations have been found in the palmoplantar specific
keratin,
keratin 9. We have analyzed six unrelated incidences of
epidermolytic palmoplantar keratoderma for mutations in their
keratin 9 genes. In two of these, we have identified mutations that alter critical residues within the highly conserved helix initiation motif at the beginning of the rod domain of
keratin 9. In a three-generation Middle Eastern kindred we found a C to T transition at
codon 162 that results in an
arginine to
tryptophan substitution at position 10 of the 1A alpha-helical domain, thus confirming this
codon as a hot spot for mutation in
keratin 9. The other mutation found involves a T to C transition at
codon 167 that results in the expression of a
serine residue in place of the normal
leucine at position 15 of the 1A segment and is the first documentation of this mutation in this gene. The identification of these substitutions extends the current catalog of disease causing mutations in
keratin 9.