Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: Implications for protein structure and clinical phenotype

Monilethrix is an hereditary hair dystrophy recently shown to be due to mut ations in the helix termination motif of two type II (basic) human hair ker atin genes, hHb1 and hHb6. It has been suggested that mutation in hHb1 prod uces a less severe phenotype. We have studied hair keratin genes and clinic al features in 18 unrelated pedigrees of monilethrix from Germany, Scotland , Northern Ireland, and Portugal, in 13 of which mutations have not previou sly been identified. By examining the rod domains of hHb1, hHb3 and hHb6, w e have identified mutations in nine of the new pedigrees, We again found th e glutamine-lysine substitution (E413K) in the helix termination motif of h Hb6 in two families, and in another, the corresponding E413K substitution i n the hHb1 gene. In four families a similar substitution E402K was present in a nearby residue. In addition two novel mutations within the helix initi ation motif of hHb6 were found in Scottish and Portuguese cases, in whom th e same highly conserved asparagine residue N114 was mutated to histidine (N 114H) or aspartic acid (N114D) residues, respectively. In four other monile thrix pedigrees mutations in these domains of hHb1, hHb3, and hHb6 were clo t found. The mutations identified predict a variety of possible structural consequences for the keratin molecule. A comparison of clinical features an d severity between cases with hHb1 and hHb6 mutations does not suggest dist inct effects on phenotype, with the possible exception of nail dystrophy, c ommoner with hHb1 defects. Other factors are required to explain the marked variation in clinical severity within and between cases.