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 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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References

  1. 1

    Heid, H.W., Werner, E. & Franke, W.W. The complement of native alpha-keratin polypeptides of hair-forming cells: a subset of eight polypeptides that differ from epithelial cytokeratins. Differentiation 32, 101–119 (1986).

    CAS  Article  Google Scholar 

  2. 2

    Lynch, M.H., O'Guin, W.M., Hardy, C., Mak, L. & Sun, T.-T. Acidic and basic hair/nail (‘hard’) keratins: their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to ‘soft’ keratins. J. Cell. Biol. 103, 2593–2606 (1986).

    CAS  Article  Google Scholar 

  3. 3

    Powell, B., Crocker, L. & Rogers, G. Hair follicle differentiation: expression, structure, and evolutionary conservation of the hair type II keratin intermediate filament gene family. Development 114, 417–433 (1992).

    CAS  PubMed  Google Scholar 

  4. 4

    Winter, H., Siry, P., Tobiasch, E. & Schweizer, J. Sequence and expression of murine type I hair keratins mHa2 and mHa3. Exp. Cell Res. 212, 190–200 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Fink, P., Rogers, M.A., Korge, B., Winter, H. & Schweizer, J. A cDNA encoding the human type I hair keratin hHa 1. Biochim. Biophys. Acta 1264, 12–14 (1995).

    Article  Google Scholar 

  6. 6

    Rogers, M.A. et al. Sequence data and chromosomal localization of human type I and type II hair keratin genes. Exp. Cell Res. 220, 357–362 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Rogers, M.A., Schweizer, J., Krieg, T. & Winter, H. A novel human type I hair keratin gene: evidence for two keratin hHa3 isoforms. Mol. Biol. Rep. 20, 155–161 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Rogers, M.A., Winter, H., Langbein, L.,, Krieg, T. & Schweizer, J. Genomic characterization of the human type I cuticular keratin hHa2 and identification of an adjacent novel type I hair keratin gene, hHa5. J. Invest. Dermatol. 107, 633–638 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Rogers, M.A. et al. Sequences and differential expression of three novel human type-II hair keratins. Differentiation 61, 187–194 (1997).

    CAS  Article  Google Scholar 

  10. 10

    McLean, W.H.I. & Lane, B. Intermediate filaments in disease. Curr. Opin. Cell Biol. 7, 118–125 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Steinert, P.M. IF-pathology: molecular consequences of rod and end domain mutations, in Intermediate Filament Structure (eds Parry, D. A.D. & Steinert, P.M.) 145–175 Springer, New York, (1995).

    Google Scholar 

  12. 12

    Mckee, G.M. & Rosen, J. Monilethrix: a clinical and histological study, with a report of six cases and a review of the literature. J. Cutan. Dis. incl. Syph. 34, 444–527 (1961).

    Google Scholar 

  13. 13

    Gummer, C.L., Dawber, P.R.P. & Swift, J.A. Monilethrix: an electron microscopic and electron histochemical study. Br. J. Dermatol. 105, 529–541 (1981).

    CAS  Article  Google Scholar 

  14. 14

    Healy, N.E. et al. A gene for monilethrix is closely linked to the type II keratin gene cluster at 12q 13. Hum. Mol. Gen. 4, 2399–2402 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Stevens, H.P. et al. Linkage of monilethrix to the trichocyte and epithelial keratin gene cluster on 12q11-q13. J. Invest. Dermatol. 106, 795–797 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Korge, B.P. et al. Monilethrix links to the keratin type II cluster at 12q13 and cloning of a possible candidate gene [abstract]. J. Invest. Dermatol. 106, 843 (1996).

    Google Scholar 

  17. 17

    De Berker, D.A.R., Ferguson, D.J.P. & Dawber, R.P.R. Monilethrix: a clinicopathological illustration of a cortical defect. Br. J. Dermatol. 128, 327–331 (1993).

    CAS  Article  Google Scholar 

  18. 18

    Ito, O.M., Hashimoto, K., Katsuuni, K. & Sato, Y. Pathogenesis of monilethrix: computer stereography and electron microscopy. J. Invest. Dermatol. 95, 186–194 (1990).

    CAS  Article  Google Scholar 

  19. 19

    McLean, W.H.I. et al. Ichthyosis bullosa of Siemens–a disease involving keratin 2e. J. Invest. Dermatol. 103, 277–281 (1994).

    CAS  Article  Google Scholar 

  20. 20

    Kremer, H. et al. Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. J. Invest. Dermatol. 103, 286–289 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Rothnagel, J.A. . et al. Mutation in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nature Genet. 7, 485–490 (1994).

    CAS  Article  Google Scholar 

  22. 22

    Hatzfeld, M. & Weber, K. Modulation of keratin intermediate filament assembly by single amino acid exchanges in the consensus sequence at the C-terminal end of the rod domain. J. Cell Sci. 99, 351–362 (1991).

    CAS  Google Scholar 

  23. 23

    Steinert, P.M., Yang, J.M., Bale, S.J. & Compton, J.G. Concurrence between the molecular overlap regions in keratin intermediate filaments and the locations of keratin mutations in genodermatoses. Biochem. Biophys. Res. Com. 197, 840–848 (1993).

    CAS  Article  Google Scholar 

  24. 24

    Rock, B., Wilkinson, J.D. & Ebling, F.J.G. Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix: in Textbook of Dermatology (eds Champion, R. H., Burton, J.L. & Ebling, F.J.G.) 1353 Blackwell Scientific, Oxford,(1992).

    Google Scholar 

  25. 25

    Richard, G., Itin, P., Lin, S.P., Bon, A. & Bale, S.J. Evidence for genetic heterogeneity in monilethrix. J Invest. Dermatol. 107, 812–814 (1996).

    CAS  Article  Google Scholar 

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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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