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A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex

Nature Genetics volume 3, pages 327–332 (1993)Cite this article

Abstract

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14–K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

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References

  1. Fine, J.-D. et al. Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa: a consensus report by the subcommittee on diagnosis and classification of the national epidermolysis bullosa registry. J. Am. Acad. Dermatol. 24, 119–135 (1991).

    Article  CAS  Google Scholar 

  2. Lin, A.N. & Carter, D.M. in Epidermolysis Bullosa: Basic and Clinical Aspects (eds Lin, A.N. & Garter, D.M.) 89–117 (Springer Verlag, New York, 1992).

    Google Scholar 

  3. Bonifas, J.M., Rothman, A.L. & Epstein, E.H., Jr. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254, 1202–1205 (1991).

    Article  CAS  Google Scholar 

  4. Coulombe, P.A. et al. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 66, 1301–1311 (1991).

    Article  CAS  Google Scholar 

  5. Lane, E.B. et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 356, 244–246 (1992).

    Article  CAS  Google Scholar 

  6. Romano, V. et al. Chromosomal assignments of human type I and type II cytokeratin genes to different chromosomes. Cytogenet. Cell Genet. 48, 148–151 (1988).

    Article  CAS  Google Scholar 

  7. Ryynänen, M., Knowiton, R.G. & Uitto, J. Mapping of epidermolysis bullosa simplex mutation to chromosome 12. Am. J. hum. Genet. 49, 978–984 (1991).

    PubMed  PubMed Central  Google Scholar 

  8. Vassar, R., Coulombe, P.A., Degenstein, L., Albers, K. & Fuchs, E. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell 64, 365–380 (1991).

    Article  CAS  Google Scholar 

  9. Coulombe, P.A., Hutton, M.E., Vassar, R. & Fuchs, E. A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. J. cell Biol. 115, 1661–1674 (1991).

    Article  CAS  Google Scholar 

  10. Coulombe, P.A., Chan, Y.-M., Albers, K. & Fuchs, E. Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro. J. cell Biol. 111, 3049–3064 (1990).

    Article  CAS  Google Scholar 

  11. Letai, A., Coulombe, P.A. & Fuchs, E. Do the ends justify the mean? Proline mutations at the ends of the keratin coiled-coil rod segment are more disruptive than internal mutations. J. cell Biol. 116, 1181–1195 (1992).

    Article  CAS  Google Scholar 

  12. Epstein, E.H., Jr. Molecular genetics of epidermolysis bullosa. Science 256, 799–803 (1992).

    Article  CAS  Google Scholar 

  13. Fuchs, E. & Coulombe, P.A. Of mice arid men: genetic skin diseases of keratin. Cell 69, 899–902 (1992).

    Article  CAS  Google Scholar 

  14. Salih, M.A.M., Lake, B.D., El Hag, M.A. & Atherton, D.J. Lethal epidermolytic epidermolysis bullosa: a new autosomal recessive type of epidermolysis bullosa. Br. J. Dermatol. 113, 135–143 (1985).

    Article  CAS  Google Scholar 

  15. Nielsen, P.G. & Sjolund, E. Epidermolysis bullosa simplex localisata associated with anodontia, hair and nail disorders: a new syndrome. Acta Derm. Veneorol. 65, 526–530 (1985).

    Google Scholar 

  16. Niemi, K.-M., Sommer, H., Kero, M., Kanerva, L. & Haltia, M. Epidermolysis bullosa simplex associated with muscular dystrophy with recessive inheritance. Arch. Dermatol. 124, 551–554 (1988).

    Article  CAS  Google Scholar 

  17. Fine, J.-D. et al. Autosomal recessive epidermolysis bullosa simplex. Arch. Dermatol. 125, 931–938 (1989).

    Article  CAS  Google Scholar 

  18. Fine, J.-D., Johnson, L., Wright, T. & Horiguchi, Y. Epidermolysis bullosa simplex: identification of a kindred with autosomal recessive transmission of the Weber-Cockayne variety. Ped. Dermatol. 6, 1–5 (1989).

    Article  CAS  Google Scholar 

  19. Rosenfeld, P.J. et al. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nature Genet. 1, 209–213 (1992).

    Article  CAS  Google Scholar 

  20. Marchuk, D., McCrohon, S. & Fuchs, E. Complete sequence of a gene encoding a human type I keratin: sequences homologous to enhancer elements in the regulatory region of the gene. Proc. natn Acad. Sci. U.S.A. 82, 1609–1613 (1985).

    Article  CAS  Google Scholar 

  21. Marchuk, D., McCrohon, S. & Fuchs, E. Remarkable conservation of structure among intermediate filament genes. Cell 39, 491–498 (1984).

    Article  CAS  Google Scholar 

  22. Korge, B.P. et al. Extensive size polymorphism of the human keratin 10 chain resides in the C-terminal V2 subdomain due to variable numbers and sizes of glycine loops. Proc. natn. Acad. Sci. U.S.A. 89, 910–914 (1992).

    Article  CAS  Google Scholar 

  23. Rosenberg, M., Raychaudhury, A., Shows, T.B., LeBeau, M.M. & Fuchs, E. A group of type I keratin genes on human chromosome 17: characterization and expression. Molec. cell Biol. 8, 722–736 (1988).

    Article  CAS  Google Scholar 

  24. Lander, E.S. & Bostein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).

    Article  CAS  Google Scholar 

  25. Compton, J.G. et al. Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q. Nature Genet. 1, 301–305 (1992).

    Article  CAS  Google Scholar 

  26. Lee, L.D. & Baden, H.P. Organization of the polypeptide chains in mammalian keratin. Nature 264, 377–379 (1976).

    Article  CAS  Google Scholar 

  27. Parry, D.A.D., Crewther, W.G., Fraser, R.D.B. & McRae, T.P. Structure of α-keratin: structural implication of the amino acid sequences of the type I and type II chain segments. J. molec. Biol. 113, 449–454 (1977).

    Article  CAS  Google Scholar 

  28. Mc Lachlan, A.D. Coiled-coil formation and sequence regularities in the helical regions of α-keratins. J. molec. Biol. 124, 297–304 (1978).

    Article  CAS  Google Scholar 

  29. Fuchs, E.V., Coppock, S.M., Green, H. & Cleveland, D.W. Two distinct classes of keratin genes and their evolutionary significance. Cell 27, 75–84 (1981).

    Article  CAS  Google Scholar 

  30. Steinert, P.M., Steven, A.C. & Roop, D.R. The molecular biology of intermediate filaments. Cell 42, 411–419 (1985).

    Article  CAS  Google Scholar 

  31. Parry, D.A.D., Steven, A.C. & Steinert, P.M. The coiled-coil molecules of intermediate filaments consist of two parallel chains in exact axial register. Biochem. Biophys. Res. Comm. 127, 1012–1018 (1985).

    Article  CAS  Google Scholar 

  32. Fraser, R.D.B., MacRae, T.P., Parry, D.A.D. & Suzuki, E. Intermediate filaments in α-keratins. Proc. natn. Acad. Sci. U.S.A. 83, 1179–1183 (1986).

    Article  CAS  Google Scholar 

  33. Steinert, P.M. & Freedberg, I.M. in Physiology, Biochemistry, and Molecular Biology of the Skin (ed. Goldsmith, L.A.) 113–147 (Oxford University Press, New York, 1992).

    Google Scholar 

  34. Coulombe, P.A. & Fuchs, E. Elucidating the early stages of keratin filament assembly. J. cell Biol. 111, 153–169 (1990).

    Article  CAS  Google Scholar 

  35. Eckert, R.L. & Rorke, E.A. The sequence of the human epidermal 58-kD (♯5) type II keratin reveals an absence of 5′ upstream sequence conservation between coexpressed epidermal keratins. DNA 7, 337–345 (1988).

    Article  CAS  Google Scholar 

  36. Rothnagel, J.A. et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 257, 1128–1130 (1992).

    Article  CAS  Google Scholar 

  37. Cheng, J. et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell 70, 811–819 (1992).

    Article  CAS  Google Scholar 

  38. Chipev, C.C. et al. A Leucine→Proline mutation in the cH1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 70, 821–828 (1992).

    Article  CAS  Google Scholar 

  39. Byers, P.H. Brittle bones-fragile molecules: disorders of collagen gene structure and expression. Trends Genet. 6, 293–300 (1990).

    Article  CAS  Google Scholar 

  40. Kuivaniemi, H., Tromp, G. & Prockop, D.J. Mutations in collagen genes: causes of rare and some common diseases in humans. Faseb J. 5, 2052–2060 (1991).

    Article  CAS  Google Scholar 

  41. Prockop, D.J. Mutations in collagen genes as a cause of connective-tissue diseases. New Engl. J. Med. 326, 540–546 (1992).

    Article  CAS  Google Scholar 

  42. Krane, S.M., Pinnell, S.R. & Erbe, R.W. Lysyl-protocollagen hydroxylase deficiency in fibroblasts from siblings with hydroxylysine-deficient collagen. Proc. natn. Acad. Sci. U.S.A. 69, 2899–2903 (1972).

    Article  CAS  Google Scholar 

  43. Nusgens, B.V. et al. Evidence for a relationship between Ehlers-Danlos type VII C in humans and bovine dermatosparaxis. Nature Genet. 1, 214–217 (1992).

    Article  CAS  Google Scholar 

  44. Pope, F.M. et al. Patients with Ehlers-Danlos syndrome type IV lack type III collagen. Proc. natn. Acad. Sci. U.S.A. 72, 1314–1316 (1975).

    Article  CAS  Google Scholar 

  45. Tromp, G. & Prockop, D. Single base mutation in the proα2(I) collagen gene that causes efficient splicing of RNA from exon 27 to exon 29 and synthesis of a shortened but in-frame proa2(I) chain. Proc. natn. Acad. Sci. U.S.A. 85, 5254–5258 (1988).

    Article  CAS  Google Scholar 

  46. Pihlajaniemi, T. et al. Osteogenesis imperfecta: cloning of a pro-α2(I) collagen gene with a frameshift mutation. J. biol. Chem. 259, 12941–12944 (1984).

    CAS  PubMed  Google Scholar 

  47. Cohn, D.H., Starman, B.J., Blumberg, B. & Byers, P.M. Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene. Am. J. hum. Genet. 46, 591–601 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Anton-Lamprecht, I., Jovanovic, V., Arnold, M.-L., Rauskolb, R. & Schenck, W. Prenatal diagnosis of genetic disorders of the skin by means of electron microscopy. Hum. Genet. 59, 392–405 (1981).

    Article  CAS  Google Scholar 

  49. Rheinwald, J.G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331–334 (1975).

    Article  CAS  Google Scholar 

  50. Chomczynski, P. & Sacchi, N. Single step method of RNA isolation of acid guanidium thibcyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  51. Gyllensten, U.B. & Erlich, H.A. Generation of single-strand DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc. natn. Acad. Sci. U.S.A. 85, 7652–7656 (1988).

    Article  CAS  Google Scholar 

  52. Dessen, P., Fondrat, C., Valencien, C. & Mugnier, C. Bisance: a French service for access to biomolecular sequences databases. Cabios. 6, 355–356 (1990).

    CAS  PubMed  Google Scholar 

  53. Lathrop, G.M., Lalouel, J.-M., Julier, C. & Ott, J. Strategies for multitocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

  54. Nakamura, Y. et al. Isolation and mapping of a polymorphic DNA sequence pYNH15 on chromosome 12q [D12S17]. Nucl. Acids Res. 16, 779 (1988).

    Article  CAS  Google Scholar 

  55. Priestley, L., Kumar, D. & Sykes, B. Amplification of the COL2A1 3′ variable region used for segregation analysis in a family with the Stickler syndrome. Hum. Genet. 85, 525–526 (1990).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratoire de Génétique moléculaire, INSERM U.91, Hôpital Henri Mondor, 94010, Créteil, France

    A. Hovnanian, E. Pollack, L. Hilal & M. Goossens

  2. Département de Biologie, Ecole Normale Supérieure, 75230, Paris, Cedex 05, France

    A. Rochat & Y. Barrandon

  3. Service de Dermatologie, Hôpital Saint-Louis, 75010, Paris, France

    C. Prost

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Hovnanian, A., Pollack, E., Hilal, L. et al. A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex. Nat Genet 3, 327–332 (1993). https://doi.org/10.1038/ng0493-327

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