MUTATIONS IN THE HAIR CORTEX KERATIN HHB6 CAUSE THE INHERITED HAIR DISEASE MONILETHRIX

Pathogenic mutations in a large number of human epithelial keratins ha ve been well characterized. However, analogous mutations in the hard a lpha-keratins of hair and nail have not yet been described. Monilethri x is a rare autosomal dominant hair defect with variable expression. H airs from affected individuals show a beaded structure of alternating elliptical nodes and constrictions (internodes). These internodes exhi bit a high propensity to weathering and fracture. Strong evidence that trichocyte keratin defects might underlie this hair disorder was prov ided by genetic linkage analyses that mapped this disease to the type- ii keratin gene cluster on 12q13. All affected individuals from a four -generation British family with monilethrix, previously linked to the type-it keratin gene cluster, as well as three unrelated single monile thrix patients, exhibited a heterozygous point mutation in the gene fa r type-Il hair cortex keratin hHb6, leading to lysine substitution of a highly conserved glutamic acid residue in the helix termination moti f (Glu 410 Lys). In a three-generation French family with monilethrix of a milder and variable phenotype, we detected another heterozygous p oint mutation in the same glutamic acid codon of hHb6, which resulted in a conservative aspartic acid substitution (Glu 410 Asp). These muta tions provide the first direct evidence for involvement of hair kerati ns in hair disease.