Abstract
Epidermolytic hyperkeratosis (EH; previously called bullous congenital ichthyosiform erythroderma) is an autosomal dominant skin disease of unknown etiology, affecting approximately 1 out of 300,000 people. It is typified by hyperkeratotic scaliness, blistering due to cytolysis within suprabasal epidermal cells, and hyperproliferation in basal cells. Histologically, EH epidermis exhibits a thickened stratum corneum and granular layer, with enlarged and irregular-shaped cells. Ultrastructurally, only suprabasal layers are affected, with three major aberrancies: (i) tonofilament clumping, (ii) nuclei and keratohyalin granules of irregular shape and size, and (iii) cell degeneration. We have discovered that transgenic mice expressing a mutant keratin 10 gene have the EH phenotype, thereby suggesting that a genetic basis for human EH residues in mutations in genes encoding suprabasal keratins K1 and K10. In addition, we show that (i) stimulation of basal cell proliferation can arise from a defect in suprabasal cells, and (ii) distortion of nuclear shape or aberrations in cytokinesis can occur when an intermediate filament network is perturbed.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ackerman A. B. Histopathologic concept of epidermolytic hyperkeratosis. Arch Dermatol. 1970 Sep;102(3):253–259. [PubMed] [Google Scholar]
- Albers K., Fuchs E. The expression of mutant epidermal keratin cDNAs transfected in simple epithelial and squamous cell carcinoma lines. J Cell Biol. 1987 Aug;105(2):791–806. doi: 10.1083/jcb.105.2.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anton-Lamprecht I. Genetically induced abnormalities of epidermal differentiation and ultrastructure in ichthyoses and epidermolyses: pathogenesis, heterogeneity, fetal manifestation, and prenatal diagnosis. J Invest Dermatol. 1983 Jul;81(1 Suppl):149s–156s. doi: 10.1111/1523-1747.ep12540961. [DOI] [PubMed] [Google Scholar]
- Anton-Lamprecht I., Schnyder U. W. Ultrastructure of inborn errors of keratinization. VI. Inherited ichthyoses--a model system for heterogeneities in keratinization disturbances. Arch Dermatol Forsch. 1974;250(3):207–227. [PubMed] [Google Scholar]
- Bonifas J. M., Rothman A. L., Epstein E. H., Jr Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science. 1991 Nov 22;254(5035):1202–1205. doi: 10.1126/science.1720261. [DOI] [PubMed] [Google Scholar]
- 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. 1990 Dec;111(6 Pt 2):3049–3064. doi: 10.1083/jcb.111.6.3049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coulombe P. A., Hutton M. E., Letai A., Hebert A., Paller A. S., Fuchs E. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell. 1991 Sep 20;66(6):1301–1311. doi: 10.1016/0092-8674(91)90051-y. [DOI] [PubMed] [Google Scholar]
- 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. 1991 Dec;115(6):1661–1674. doi: 10.1083/jcb.115.6.1661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coulombe P. A., Kopan R., Fuchs E. Expression of keratin K14 in the epidermis and hair follicle: insights into complex programs of differentiation. J Cell Biol. 1989 Nov;109(5):2295–2312. doi: 10.1083/jcb.109.5.2295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eichner R., Bonitz P., Sun T. T. Classification of epidermal keratins according to their immunoreactivity, isoelectric point, and mode of expression. J Cell Biol. 1984 Apr;98(4):1388–1396. doi: 10.1083/jcb.98.4.1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Franke W. W., Schiller D. L., Hatzfeld M., Winter S. Protein complexes of intermediate-sized filaments: melting of cytokeratin complexes in urea reveals different polypeptide separation characteristics. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7113–7117. doi: 10.1073/pnas.80.23.7113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fuchs E., Green H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell. 1980 Apr;19(4):1033–1042. doi: 10.1016/0092-8674(80)90094-x. [DOI] [PubMed] [Google Scholar]
- Holbrook K. A., Dale B. A., Sybert V. P., Sagebiel R. W. Epidermolytic hyperkeratosis: ultrastructure and biochemistry of skin and amniotic fluid cells from two affected fetuses and a newborn infant. J Invest Dermatol. 1983 Apr;80(4):222–227. doi: 10.1111/1523-1747.ep12534504. [DOI] [PubMed] [Google Scholar]
- Kopan R., Fuchs E. A new look into an old problem: keratins as tools to investigate determination, morphogenesis, and differentiation in skin. Genes Dev. 1989 Jan;3(1):1–15. doi: 10.1101/gad.3.1.1. [DOI] [PubMed] [Google Scholar]
- Lane E. B., Rugg E. L., Navsaria H., Leigh I. M., Heagerty A. H., Ishida-Yamamoto A., Eady R. A. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature. 1992 Mar 19;356(6366):244–246. doi: 10.1038/356244a0. [DOI] [PubMed] [Google Scholar]
- 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. 1992 Mar;116(5):1181–1195. doi: 10.1083/jcb.116.5.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Natl Acad Sci U S A. 1985 Mar;82(6):1609–1613. doi: 10.1073/pnas.82.6.1609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
- Rieger M., Franke W. W. Identification of an orthologous mammalian cytokeratin gene. High degree of intron sequence conservation during evolution of human cytokeratin 10. J Mol Biol. 1988 Dec 20;204(4):841–856. doi: 10.1016/0022-2836(88)90045-9. [DOI] [PubMed] [Google Scholar]
- Roop D. R., Huitfeldt H., Kilkenny A., Yuspa S. H. Regulated expression of differentiation-associated keratins in cultured epidermal cells detected by monospecific antibodies to unique peptides of mouse epidermal keratins. Differentiation. 1987;35(2):143–150. doi: 10.1111/j.1432-0436.1987.tb00162.x. [DOI] [PubMed] [Google Scholar]
- Steinert P. M., Rice R. H., Roop D. R., Trus B. L., Steven A. C. Complete amino acid sequence of a mouse epidermal keratin subunit and implications for the structure of intermediate filaments. Nature. 1983 Apr 28;302(5911):794–800. doi: 10.1038/302794a0. [DOI] [PubMed] [Google Scholar]
- 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. 1991 Jan 25;64(2):365–380. doi: 10.1016/0092-8674(91)90645-f. [DOI] [PubMed] [Google Scholar]
- Vassar R., Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 1991 May;5(5):714–727. doi: 10.1101/gad.5.5.714. [DOI] [PubMed] [Google Scholar]
- Weiss R. A., Eichner R., Sun T. T. Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48- and 56-kdalton keratin as molecular markers for hyperproliferative keratinocytes. J Cell Biol. 1984 Apr;98(4):1397–1406. doi: 10.1083/jcb.98.4.1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilgram G. F., Caulfield J. B. An electron microscopic study of epidermolytic hyperkeratosis. With a special note on the keratinosome as the "fourth" structural factor in the formation of the horny layer. Arch Dermatol. 1966 Aug;94(2):127–143. doi: 10.1001/archderm.94.2.127. [DOI] [PubMed] [Google Scholar]