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
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Winter, H., Rogers, M., Langbein, L. et al. Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet 16, 372–374 (1997). https://doi.org/10.1038/ng0897-372
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