A MUTATIONAL HOTSPOT IN THE 2B DOMAIN OF HUMAN HAIR BASIC KERATIN-6 (HHB6) IN MONILETHRIX PATIENTS

Monilethrix is an inherited hair dystrophy in which affected, fragile, hairs have an unique beaded morphology. Ultrastructural studies sugge st a defect in filament structure in the cortex of the hair, and the h ard keratins of hair and nail are thus candidate genes. In several fam ilies with autosomal dominant monilethrix, the disorder has been linke d to the type II keratin gene cluster at chromosome 12q13. Recently, c ausative mutations in the critical helix termination motif in the 2B d omain of the human hair basic keratin 6 (hHb6) have been identified. W e now report the results of sequencing this domain in 13 unrelated fam ilies or cases with monilethrix. Five of the 13 had the same mutation as previously found, a G to A transversion leading to a lysine for glu tamic acid substitution (E413K) in the 2B domain (residue 117 of the 2 B helix) ofhHb6. The mutation was confirmed by a restriction fragment length polymorphism assay developed for this purpose, and, as this mut ation is evidently a common cause of the syndrome, for use in screenin g other cases. In eight families or cases, however, including three in whom linkage data are consistent with a defect at the type II keratin locus, no mutation was found in this domain ofhHb6.