title: Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix.
abstract: Pathogenic mutations in a large number of human epithelial keratins have been well characterized. However, analogous mutations in the hard alpha-keratins of hair and nail have not yet been described. Monilethrix is a rare autosomal dominant hair defect with variable expression. Hairs from affected individuals show a beaded structure of alternating elliptical nodes and constrictions (internodes). These internodes exhibit a high prospensity to weathering and fracture. Strong evidence that trichocyte keratin defects might underlie this hair disorder was provided 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-II keratin gene cluster, as well as three unrelated single monilethrix patients, exhibited a heterozygous point mutation in the gene for type-II hair cortex keratin hHb6, leading to lysine substitution of a highly conserved glutamic acid residue in the helix termination motif (Glu 410 Lys). In a three-generation French family with monilethrix of a milder and variable phenotype, we detected another heterozygous point mutation in the same glutamic acid codon of hHb6, which resulted in a conservative aspartic acid substitution (Glu 410 Asp). These mutations provide the first direct evidence for involvement of hair keratins in hair disease.
authors.affiliation: Division of Tumour Cell Regulation, German Cancer Research Center, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Winter
authors.forename: M A
authors.initials: MA
authors.lastname: Rogers
authors.forename: L
authors.initials: L
authors.lastname: Langbein
authors.forename: H P
authors.initials: HP
authors.lastname: Stevens
authors.forename: I M
authors.initials: IM
authors.lastname: Leigh
authors.forename: C
authors.initials: C
authors.lastname: Labrèze
authors.forename: S
authors.initials: S
authors.lastname: Roul
authors.forename: A
authors.initials: A
authors.lastname: Taieb
authors.forename: T
authors.initials: T
authors.lastname: Krieg
authors.forename: J
authors.initials: J
authors.lastname: Schweizer
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D018698:Glutamic Acid; D006201:Hair Diseases / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007633:Keratins / Q000235:genetics*; D008239:Lysine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: D018698:Glutamic Acid; D007633:Keratins; D008239:Lysine