Original Article

Journal of Investigative Dermatology (1994) 102, 390–394; doi:10.1111/1523-1747.ep12371801

Epidermolytic Hyperkeratosis: Applied Molecular Genetics

Alan N Moshell, John J DiGiovanna1 and Sherri J Bale2

  1. 1Dermatology Branch, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, Bethesda, Maryland, U.S.A.
  2. 2Genetic Studies Section, Skin Biology Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, Maryland, U.S.A.
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Abstract

Epidermolytic hyperkeratosis is an autosomal dominant ichthyosis characterized by blistering, especially at birth and during childhood, and hyperkeratosis. Epidermolytic hyperkeratosis presents striking clinical heterogeneity, particularly between families. Several avenues of research have implicated an abnormality of epidermal differentiation in the pathogenesis of this disease. In a three-generation family with 20 affected individuals, we tested a variety of candidate loci and identified linkage to the type II keratin region on chromosome 12. Further investigation revealed a mutation in the H1 subdomain of the keratin 1 gene as the cause of EHK in this family. Because keratin 10 is the co-expressed partner of keratin 1, it was not surprising when abnormalities in keratin 10 were found in other families with EHK. We have examined 52 patients from 21 families and have identified at least six clinical phenotypes. The most useful distinguishing feature was the presence or absence of severe hyper keratosis of the palms and soles. We and others are continuing to search for and characterize mutations in keratin 1 and 10 in patients with epidermolytic hyperkeratosis. Correlation of the clinical disease types with the specific mutations should lead to a better understanding of the relationship between keratin structure and function in normal and diseased epidermis.

Keywords:

ichthyosis, keratin, genodermatosis

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References

  1. Williams, ML, Elias, PM: Disorders of Cornification. In: Alper JC (ed.). Dermatologic Clinics 1987, Philadelphia, WB Saunders, pp 155–178,
  2. Feinstein, A, Ackerman, AB, Ziprkowski, L: Histology of autosomal dominant ichthyosis vulgaris and x-linked ichthyosis. Arch Dermatol 1970 101: 525–527,
  3. Goldsmith, LA: The ichthyoses. Prog Med Genet 1976 1: 185–240,  | PubMed | ISI | ChemPort |
  4. Wells, RS, Kerr, CB: Clinical features of autosomal dominant and x-linked recessive ichthyosis in an English population. Br Med J 1966 1: 947–950,  | ISI |
  5. Wells, RS, Kerr, CB: Genetic classification of ichthyosis. Arch Dermatol 1965 92: 1–5,
  6. Lykkesfeldt, G, Hoyer, H, Ibsen, HH: Steroid sulfatase deficiency disease. Clin Genet 1985 28: 231–237,
  7. Traupe, H, Happle, R: Clinical spectrum of steroid sulfatase deficiency: x-linked recessive ichthyosis, birth complications and cryptorchidism. Eur J Pediatr 1983 140: 19–21,
  8. Epstein, EH, Jr Bonifas, JM: Recessive x-linked ichthyosis: lack of immunologically detectable steroid sulfatase enzyme protein. Hum Genet 1985 71: 201–205,
  9. Koppe, JG, Ilsen, A, Rijken, Y, De Groot, WP, Jobsis, AC: X-linked ichthyosis. A sulfatase deficiency. Arch Dis Child 1978 53: 803–806,
  10. Shapiro, LJ, Weiss, R, Webster, D, France, JT: X-linked ichthyosis due to steroid sulfatase deficiency. Lancet 1978 1: 70–72,  | PubMed | ISI | ChemPort |
  11. Steinberg, D: Phytanic acid storage disease: Refsum's syndrome. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al (ed.). The Metabolic Basis of Inherited Disease, 5th ed 1983, McGraw-Hill, New York, pp 731–747,
  12. Chanarin, I, Patel, A, Slavin, G: Neutral lipid storage disease: a new disorder of lipid metabolism. Br Med J 1975 1: 553–555,  | PubMed | ISI | ChemPort |
  13. Dorfman, ML, Hershko, C, Eisenberg, S: Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 1974 110: 261–266,
  14. Williams, ML, Koch, TK, O'Donnell, JJ: Ichthyosis and neutral lipid storage disease. Am J Med Genet 1985 20: 711–726,  | Article | PubMed | ISI | ChemPort |
  15. Kolodny, EH, Moser, H: Sulfatide lipidosis: metachromatic leukodystrophy. In: Stanbury JF, Wyngaarden JB, Frederickson DS, et al (eds.) The Metabolic Basis of Inherited Disease 1983, McGraw-Hill, New York, pp 881–905,
  16. Frost, P, Van Scott, EJ: Ichthyosiform dermatoses: classification based on anatomic and biometric observations. Arch Derm 1966 94: 113–126,
  17. Anton-Lamprecht, IJ: Genetically induced abnormalities of epidermal differentiation and ultrastructure in ichthyoses and epidermolysis: pathogenesis, heterogeneity, fetal manifestation, and prenatal diagnosis. J Invest Dematol 1983 81: 149–156,
  18. Ishida-Yamamoto, A, Leigh, IM, Lane, EB: Selective expression of the differentiation specific keratins K1 and K10 in the tonofilament clumps of bullous ichthyosis (epidermolytic hyperkeratosis). J Invest Dermatol 1992 99: 10–25,
  19. Blanchet-Bardon, C, Lamprecht, IJ, Schnyder, UW: Erythrodermic congenitale ichthyosiforme bulleuse. Controle ultrastructural du traitement par l'ether aromatique de l'acide retinoique. Ann Dermatol Venereol 1977 104: 648–653,  | PubMed | ChemPort |
  20. Zhou, X-M, Idler, WW, Steven, AC, Roop, DR, Steinert, PM: The complete sequence of human intermediate filament chain keratin 10. J Biol Chem 1988 263: 15584–15589,  | PubMed | ISI | ChemPort |
  21. Johnson, LD, Idler, WW, Zhou, C-M, Roop, DR, Steinert, PM: Structure of a gene for the human epidermal 67-kda keratin. Proc Natl Acad Sci USA 1988 82: 1896–1900,
  22. Rieger, M, Jorcano, JL, Franke, WW: Complete sequence of a bovine type I cytokeratin gene: conserved and variable intron positions in genes of polypeptides of the same cytokeratin subfamily. EMBO J 1985 4: 2261–2267,  | PubMed | ISI | ChemPort |
  23. McKinley-Grant, LJ, Idler, WW, Bernstein, IA, Parry, DAD, Cannizzaro, L, Croce, CM, Huebner, K, Lessin, SR, Steinert, PM: Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. Proc Natl Acad Sci USA 1989 86: 4848–4852,  | PubMed | ChemPort |
  24. Gan, SQ, McBride, OW, Idler, WW, Markova, N, Steinert, PM: Structure, organization and polymorphisms of the human profilaggrin gene. Biochemistry 1990 29: 9432–9440,  | Article | PubMed | ISI | ChemPort |
  25. Yoneda, K, Hohl, D, McBride, OW, Wang, M, Cehrs, KV, Idler, WW, Steinert, PM: The human loricrin gene. J Biol Chem 1992 267: 18063–18066,
  26. Hohl, D, Mehrel, T, Lichti, U, Turner, ML, Roop, DR, Steinert, PM: Characterization of human loricrin. J Biol Chem 1991 266: 6626–6636,  | PubMed | ISI | ChemPort |
  27. Eckert, RL, Green, H: Structure and evolution of the human involucrin gene. Cell 1986 46: 583–589,  | Article | PubMed | ISI | ChemPort |
  28. Kim, IG, McBride, OW, Wang, M, Kim, SJ, Idler, WW, Steinert, PM: Structure and organization of the human transglutaminase 1 gene. J Biol Chem 1992 367: 7710–7717,
  29. Epstein, EH, Jr: Molecular genetics of epidermolysis bullosa. Science 1992 256: 799–804,  | PubMed | ISI | ChemPort |
  30. Vassar, R, Coulombe, PA, Degenstein, L, Albers, K, Fuchs, E: Mutant keratin expression in transgenic mice causes marked abnormalities resembling human genetic skin disease. Cell 1991 64: 365–380,  | Article | PubMed | ISI | ChemPort |
  31. Fuchs, E, Esteves, RA, Coulombe, PA: Transgenic mice expressing a mutant keratin 10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis. Proc Natl Acad Sci USA 1992 89: 6906–6910,  | PubMed | ChemPort |
  32. Compton, JG, DiGiovanna, JJ, Santucci, SK, Kearns, KS, Amos, CI, Abangan, DL, Korge, BP, McBride, OW, Steinert, PM, Bale, SJ: Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q. Nature Genet 1992 1: 301–305,  | Article |
  33. Lessin, SR, Huebner, K, Isobe, M, Croce, CM, Steinert, PM: Chromosomal mapping of human keratin genes: evidence for nonlinkage. J Invest Dermatol 1988 91: 572–578,  | Article | PubMed | ISI | ChemPort |
  34. Romano, V, Bosco, P, Rocchi, M, Costa, G, Leube, RE, Franke, WW, Romeo, G: Chromosomal assignments of human type I and type II cytokeratin genes to different chromosomes. Cytogenet Cell Genet 1988 48: 148–151,  | PubMed | ISI | ChemPort |
  35. Barletta, C, Batticane, N, Ragusa, RM, Leube, R, Peschle, C, Romano, V: Subchromosomal localization of two human cytokeratin genes (KRT4 and KRT15) by in situ hybridization. Cytogenet Cell Genet 1990 54: 148–150,  | PubMed | ISI | ChemPort |
  36. Bonifas, JM, Bare, JW, Chen, MA, Lee, MK, Slater, CA, Goldsmith, LA, Epstein, EH: Linkage of the epidermolytic hyperkeratosis phenotype and the region of the type II keratin gene cluster on chromosome 12. J Invest Dermatol 1992 99: 524–527,  | Article | PubMed | ISI | ChemPort |
  37. Chipev, CC, Korge, BP, Markova, N: A leucine-proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 1992 70: 821–828,  | Article | PubMed | ISI | ChemPort |
  38. Steinert, PM, Marekov, LN, Fraser, RDB, Parry, DAD: Keratin intermediate filament structure. J Mol Biol 1993 230: 436–452,  | Article | PubMed | ISI | ChemPort |
  39. Steinert, PM, Parry, DAD: The conserved H1 domain of the type II keratin chain plays an essential role in the alignment of nearest-neighbor molecules in mouse and human keratin 1/keratin 10 intermediate filaments at the two- to four-molecule level of structure. J Biol Chem 1993 268: 2678–2887,
  40. Rothnagel, JA, Dominey, AM, Dempsey, LD, Longley, MA, Greenhalgh, DA, Gagne, TA, Huber, M: Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992 257: 1128–1130,  | PubMed | ISI | ChemPort |
  41. Yang, J-M, Chipev, CC, Steinert, PM, Compton, JG: Is palmo-plantar involvement in epidermolytic hyperkeratosis associated with specific keratin mutations? (abstr). J Invest Dermatol 1993 100: 581,
  42. Cheng, J, Syder, AJ, Yu, Q-C, Letai, A, Paller, AS, Fuchs, E: The genetic basis for epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell 1992 70: 811–819,  | Article | PubMed | ISI | ChemPort |
  43. Coulombe, PA, Hutton, ME, Letai, A, Heber, A, Paller, AS, Fuchs, E: Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 1991 66: 1301–1311,  | Article | PubMed | ISI | ChemPort |
  44. Brocq, L: Erythrodermic congenitale ichthyosiforme avec hyperepidermotrophic. Ann Dermatol Syph (Paris) 1902 4: 1–31,
  45. Siemens, HW: Dichtung und Wahrbeit uber die "Ichthyosis bullosa", mit Bemerkungen zur Systemik der Epidermolysen. Arch Dermatol Syph 1937 175: 590–608,
  46. Curth, HO, Macklin, MT: The genetic basis of various types of ichthyosis in a family group. Am J Hum Genet 1954 6: 371–382,  | PubMed | ISI | ChemPort |

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