Keratin 14 point mutations at codon 119 of helix 1A resulting in differentepidermolysis bullosa simplex phenotypes

Epidermolysis bullosa simplex is a heterogeneous group of inherited bullous disorders due to mutations in keratins 5 and 14. We report two different m utations in keratin 14 at codon 119 of the helix initiation peptide, each w ith different phenotypic expression. One, a sporadic case that clinically r esembles Dowling-Meara epidermolysis bullosa simplex, resulted from convers ion of methionine to threonine (M119T). The other, a multigeneration family with the Koebner phenotype, resulted from a previously unreported methioni ne to valine substitution (M119V). We suggest that loss of hydrophobicity d uring conversion of methionine to threonine is responsible for the more sev ere presentation of the first family, whereas maintenance of the hydrophobi c nature of the amino acid with conversion to valine resulted in a less sev ere variant of epidermolysis bullosa simplex. Although most prior mutations in the highly conserved boundary motif of the a-helix have resulted in the Dowling-Meara subtype, our findings confirm that it is not always possible to predict the epidermolysis bullosa simplex severity on the basis of the location of the mutation along the keratin polypeptide. The specific amino acid substitution may be more critical in some cases.