Monilethrix: A novel mutation (Glu402Lys) in the helix termination motif and the first causative mutation (Asn114Asp) in the helix initiation motif of the type II hair keratin hHb6

Monilethrix, a rare human hair disorder with autosomal dominant transmissio n, can be caused by mutations in hair keratins, Up to now, causative mutati ons have only been found in two type II cortex keratins, hHb6 and hHb1, In these hair keratins, the helix termination motif, HTM, was the only site in which mutations were located. The most frequent mutation, which has been f ound in 22 cases, was a Glu413Lys substitution in hHb6, whereas other mutat ions, i.e,, hHb6 Glu413Asp, hHb1 Glu413Lys, and hHb1 Glu402Lys, have been r eported in a distinctly lower number of cases. In this study, we describe t he equivalent of the hHb1 Glu402Lys mutation in the HTM of cortex keratin h Hb6, The mutation occurred in an American family in which it could only be detected in one clinically affected individual. Thus the underlying G-->A t ransition represents a spontaneous germ-line mutation in the hHb6 gene, Thi s new mutation indicates that both the hHb6/hHb1 Glu413Lys substitution and the hHb6/hHb1 Glu402Lys substitution, represent mutational hotspots in the HTM of type II cortex keratins, However, we also describe a monilethrix-ca using mutation in the helix initiation motif, HIM, of the cortex keratin hH b6. The critical Asn114Asp substitution was only found in affected members of a Large Swedish three-generation family. Considering that since childhoo d, half of the affected individuals suffer from complete baldness and folli cular keratosis, the new HIM mutation seems to be associated with a rather severe disease phenotype, In conclusion, our data strongly suggest that mon ilethrix is a disease of the hair cortex, whose etiology is interesting in that causative mutations seem to be restricted to type II hair keratins.