Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix

• Published in: Nature genetics Vol. 16; no. 4; pp. 372 - 374
• Main Authors: Winter, Hermelita, Labrèze, Christine, Roul, Sylvie, Taieb, Alain, Krieg, Thomas, Schweizer, Jürgen, Stevens, Howard P, Langbein, Lutz, Rogers, Mike A, Leigh, Irene M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.1997; Nature Publishing Group
• Subjects: Adolescent; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Dermatology; Female; Gene Function; Glutamic Acid; Hair and nails disorders; Hair Diseases - genetics; Hair Diseases - pathology; Heterozygote; Human Genetics; Humans; Keratins - genetics; letter; Lysine; Male; Medical sciences; Middle Aged; Mutation; Pedigree; Genetic mapping; Human; Skin disease; Linkage; Monilethrix; Family study; Chromosome C12; Genetic disease; Proteins; Hair (head); Keratin; Gene; Genetics; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng0897-372

Pathogenic mutations in a large number of human epithelial keratins have been well characterized. However, analogous mutations in the hard α-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 propensity 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-ll keratin gene cluster on 12q13. All affected individuals from a four-generation British family with monilethrix, previously linked to the type-ll keratin gene cluster, as well as three unrelated single monilethrix patients, exhibited a heterozygous point mutation in the gene for type-ll 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