American Journal of Clinical Dermatology

, Volume 4, Issue 5, pp 347–364

The Molecular Genetics of Keratin Disorders

Review Article


Keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells. They are expressed in pairs in a tissue- and differentiation-specific fashion. Epidermolysis bullosa simplex (EBS) was the first human disorder to be associated with keratin mutations. The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14. Dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma.

Identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells. For example, in bullous congenital ichthyosiform erythroderma, clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins, K1 and K10. Mutations have now been identified in 18 keratins, all of which produce a fragile cell phenotype. These include ichthyosis bullosa of Siemens (K2e), epidermolytic palmoplantar keratoderma (K1, K9), pachyonychia congenita (K6a, K6b, K16, K17), white sponge nevus (K4, K13), Meesmann’s corneal dystrophy (K3, K12), cryptogenic cirrhosis (K8, K18) and monilethrix (hHb6, hHb1).

In general, these disorders are inherited as autosomal dominant traits and the mutations act in a dominant-negative manner. Therefore, treatment in the form of gene therapy is difficult, as the mutant gene needs to be inactivated. Ways of achieving this are actively being studied. Reliable mutation detection methods from genomic DNA are now available. This enables rapid screening of patients for keratin mutations. For some of the more severe phenotypes, prenatal diagnosis may be requested and this can now be performed from chorionic villus samples at an early stage of the pregnancy.

This review article describes the discovery of, to date, mutations in 18 keratin genes associated with inherited human diseases.


  1. 1.
    Hesse M, Magin TM, Weber K. Genes for intermediate filament proteins and the draft sequence of the human genome: novel keratin genes and a surprisingly high number of pseudogenes related to keratin genes 8 and 18. J Cell Sci 2001; 114 (Pt 14): 2569–2575PubMedGoogle Scholar
  2. 2.
    Romano V, Bosco P, Rocchi M, et al. Chromosomal assignments of human type I and type II cytokeratin genes to different chromosomes. Cytogenet Cell Genet 1988; 48: 148–151PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenberg M, RayChaudhury A, Shows T, et al. A group of type I keratin genes on human chromosome 17: characterization and expression. Mol Cell Biol 1988; 8: 722–736PubMedGoogle Scholar
  4. 4.
    Rosenberg M, Fuchs E, LeBeau MM, et al. Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12. Cytogenet Cell Genet 1991; 57: 33–38PubMedCrossRefGoogle Scholar
  5. 5.
    Waseem A, Alexander CM, Steel JB, et al. Embryonic simple epithelial keratins 8 and 18: chromosomal location emphasizes difference from other keratin pairs. New Biol 1990; 2 (5): 464–478PubMedGoogle Scholar
  6. 6.
    Smith T A, Strelov SV, Burkhard P, et al. Sequence comparisons of intermediate filament chains: evidence of a unique functional/structural role for coiled-coil segment 1A and linker L1. J Struct Biol 2002; 137: 128–145PubMedCrossRefGoogle Scholar
  7. 7.
    Steinert PM, Yang JM, Bale SJ, et al. Concurrence between the molecular overlap regions in keratin intermediate filaments and the locations of keratin mutations in genodermatoses. Biochem Biophys Res Commun 1993; 197 (2): 840–848PubMedCrossRefGoogle Scholar
  8. 8.
    Steinert PM. Structure, function and dynamics of keratin intermediate filaments. J Invest Dermatol 1993; 100 (6): 729–734PubMedCrossRefGoogle Scholar
  9. 9.
    Steinert PM, North AC, Parry DA. Structural features of keratin intermediate filaments. J Invest Dermatol 1994; 103 (5 Suppl.): 19S–24SPubMedCrossRefGoogle Scholar
  10. 10.
    Steven AC, Hainfeld JF, Trus BL, et al. Epidermal keratin filaments assembled in vitro have masses per unit length that scale according to average subunit mass: structural basis for homologous packing of subunits in intermediate filaments. J Cell Biol 1983; 97: 1939–1944PubMedCrossRefGoogle Scholar
  11. 11.
    Herrmann H, Strelkov SV, Feja B, et al. The intermediate filament protein consensus motif of helix 2B: its atomic structure and contribution to assembly. J Mol Biol 2000; 298 (5): 817–832PubMedCrossRefGoogle Scholar
  12. 12.
    Moll R, Franke WW, Schiller DL, et al. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31 (1): 11–24PubMedCrossRefGoogle Scholar
  13. 13.
    McKenna KE, Walsh MY, Bingham EA. Epidermolysis bullosa in Northern Ireland. Br J Dermatol 1992; 1277 (4): 318–321PubMedCrossRefGoogle Scholar
  14. 14.
    Fine JD. Epidermolysis bullosa: application of epidemiologic principles to the study of a group of rare diseases via a disease registry. Dermatol Clin 1995; 13 (3): 659–670PubMedGoogle Scholar
  15. 15.
    Horn HM, Priestley GC, Eady RA, et al. The prevalence of epidermolysis bullosa in Scotland. Br J Dermatol 1997; 136 (4): 560–564PubMedCrossRefGoogle Scholar
  16. 16.
    Dowling GB, Meara RH. Epidermolysis bullosa resembling juvenile dermatitis herpetiformis. Br J Dermatol 1954; 66: 139–143PubMedCrossRefGoogle Scholar
  17. 17.
    Fine JD, Bauer EA, Briggaman RA, 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 1991; 24: 119–135PubMedCrossRefGoogle Scholar
  18. 18.
    Anton-Lamprecht I, Schnyder UW. Epidermolysis bullosa herpetiformis Dowling-Meara: report of a case and pathomorphogenesis. Dermatologica 1982; 164: 221–235PubMedCrossRefGoogle Scholar
  19. 19.
    Ishida-Yamamoto A, McGrath JA, Chapman SJ, et al. Epidermolysis bullosa simplex (Dowling-Meara type) is a genetic disease characterized by an abnormal keratin filament network involving keratins K5 and K14. J Invest Dermatol 1991; 97 (6): 959–968PubMedCrossRefGoogle Scholar
  20. 20.
    McGrath JA, Ishida-Yamamoto A, Tidman MJ, et al. Epidermolysis bullosa simplex (Dowling-Meara): a clinicopathological review. Br J Dermatol 1992; 126: 421–430PubMedCrossRefGoogle Scholar
  21. 21.
    Weber F. Recurrent bullous eruptions on the feet in a child. Froc R Soc Med 1926; 19: 72Google Scholar
  22. 22.
    Cockayne E. Recurrent bullous eruptions of the feet. Br J Dermatol 1938; 55: 358–362CrossRefGoogle Scholar
  23. 23.
    Pearson RW. Clinicopathologic types of epidermolysis bullosa and their nondermatological complications. Arch Dermatol 1988; 124 (5): 718–725PubMedCrossRefGoogle Scholar
  24. 24.
    Koebner H. Hereditaere Anlage zur Blasenbildung (Epidermolysis bullosa hereditaria). Dtsch Med Wochenschr 1886; 12: 21–22CrossRefGoogle Scholar
  25. 25.
    Coulombe P A, Hutton ME, Vassar R, et al. A function for keratins and a common thread among different types of epidermolysis bullosa simplex diseases. J Cell Biol 1991; 115: 1661–1674PubMedCrossRefGoogle Scholar
  26. 26.
    Vassar R, Coulombe P A, Degenstein L, et al. Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease. Cell 1991; 64: 365–380PubMedCrossRefGoogle Scholar
  27. 27.
    Bonifas JM, Rothman AL, Epstein Jr EH. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 1991; 254 (5035): 1202–1205PubMedCrossRefGoogle Scholar
  28. 28.
    Coulombe PA, Hutton ME, Letai A, et al. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analysis. Cell 1991; 66: 1301–1311PubMedCrossRefGoogle Scholar
  29. 29.
    Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 1992; 356 (6366): 244–246PubMedCrossRefGoogle Scholar
  30. 30.
    Albers K, Fuchs E. The expression of mutant epidermal keratin cDNAs transfected in simple epithelial and squamous cell carcinoma lines. J Cell Biol 1987; 105: 791–806PubMedCrossRefGoogle Scholar
  31. 31.
    Albers K, Fuchs E. Expression of mutant keratin cDNAs in epithelial cells reveals possible mechanisms for initiation and assembly of intermediate filaments. J Cell Biol 1989; 108: 1477–1493PubMedCrossRefGoogle Scholar
  32. 32.
    Coulombe P A, Chan YM, Albers K, et al. Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro. J Cell Biol 1990; III (6 Pt 2): 3049–3064CrossRefGoogle Scholar
  33. 33.
    Bonifas JM, Rothman AL, Epstein E. Linkage of epidermolysis bullosa simplex to probes in the region of keratin gene clusters on chromosomes 12q and 17q [abstract]. J Invest Dermatol 1991; 96: 550aGoogle Scholar
  34. 34.
    Ryynanen M, Knowlton RG, Uitto J. Mapping of epidermolysis-bullosa simplex mutation to chromosome-12. Am J Hum Genet 1991; 49 (5): 978–984PubMedGoogle Scholar
  35. 35.
    Hoyheim B, Gedde-Dahl T, Olaisen B. Linkage studies in epidermolysis bullosa simplex [abstract]. J Invest Dermatol 1992; 98: 397aGoogle Scholar
  36. 36.
    McKenna KE, Hughes AE, Nevin NC. Linkage of epidermolysis bullosa simplex to keratin gene loci. J Med Genet 1992; 29: 568–570PubMedCrossRefGoogle Scholar
  37. 37.
    Corden LD, McLean WH. Human keratin diseases: hereditary fragility of specific epithelial tissues. Exp Dermatol 1996; 5 (6): 297–307PubMedCrossRefGoogle Scholar
  38. 38.
    Cooper DN, Krawczak M. Human gene mutation. Oxford: BIOS Scientific Publishers Ltd, 1993Google Scholar
  39. 39.
    Hut PH, v d Vlies P, Jonkman MF, et al. Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot mutation analysis. J Invest Dermatol 2000; 114 (4): 616–619PubMedCrossRefGoogle Scholar
  40. 40.
    Rugg EL, Baty D, Shemanko CS, et al. DNA based prenatal testing for the skin blistering disorder epidermolysis bullosa simplex. Prenat Diagn 2000; 20 (5): 371–377PubMedCrossRefGoogle Scholar
  41. 41.
    Muller FE, Anton-Lamprecht I, Kuster W, et al. A premature stop codon mutation in the 2B helix termination peptide of keratin 5 in a German epidermolysis bullosa simplex Dowling-Meara case. J Invest Dermatol 1999; 112 (6): 988–990PubMedCrossRefGoogle Scholar
  42. 42.
    Rugg EL, Rachet-Prehu MO, Rochat A, et al. Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex. Eur J Hum Genet 1999; 7 (3): 293–300PubMedCrossRefGoogle Scholar
  43. 43.
    Livingston RJ, Sybert VP, Smith LT, et al. Expression of a truncated keratin 5 may contribute to severe palmar: plantar hyperkeratosis in epidermolysis bullosa simplex patients. J Invest Dermatol 2001; 116 (6): 970–974PubMedCrossRefGoogle Scholar
  44. 44.
    Ehrlich P, Sybert VP, Spencer A, et al. A common keratin 5 gene mutation in epidermolysis bullosa simplex Weber-Cockayne. J Invest Dermatol 1995; 104 (5): 877–879PubMedCrossRefGoogle Scholar
  45. 45.
    Chen MA, Bonifas JM, Matsumura K, et al. A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simplex: DE375. Hum Molec Genet 1993; 2 (11): 1971–1972PubMedCrossRefGoogle Scholar
  46. 46.
    Shemanko CS, Mellerio JE, Tidman MJ, et al. Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14). J Invest Dermatol 1998; 111 (5): 893–895PubMedCrossRefGoogle Scholar
  47. 47.
    Cummins RE, Klingberg S, Wesley J, et al. Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes. J Invest Dermatol 2001; 117 (5): 1103–1107PubMedCrossRefGoogle Scholar
  48. 48.
    Chen H, Bonifas JM, Matsumura K, et al. Keratin 14 gene mutations in patients with epidermolysis bullosa simplex. J Invest Dermatol 1995; 105 (4): 629–632PubMedCrossRefGoogle Scholar
  49. 49.
    Hu ZL, Smith L, Martins S, et al. Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex: increased severity of disease in a homozygote. J Invest Dermatol 1997; 109 (3): 360–364PubMedCrossRefGoogle Scholar
  50. 50.
    Stephens K, Zlotogorski A, Smith L, et al. Epidermolysis bullosa simplex: a keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function. Am J Hum Genet 1995; 56 (3): 577–585PubMedGoogle Scholar
  51. 51.
    Fischer T, Gedde-Dahl Jr T. Epidermolysis bullosa simplex and mottled pigmentation: a new dominant syndrome: 1. clinical and histological features. Clin Genet 1979; 15 (3): 228–238PubMedCrossRefGoogle Scholar
  52. 52.
    Uttam J, Hutton E, Coulombe PA, et al. The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci USA 1996; 93 (17): 9079–9084PubMedCrossRefGoogle Scholar
  53. 53.
    Irvine AD, Rugg EL, Lane EB, et al. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol 2001; 144 (1): 40–45PubMedCrossRefGoogle Scholar
  54. 54.
    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 1993; 3: 327–332PubMedCrossRefGoogle Scholar
  55. 55.
    Chan Y, Anton-Lamprecht I, Yu QC, et al. A human keratin 14 “knockout”: the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein. Genes Dev 1994; 8 (21): 2574–2587PubMedCrossRefGoogle Scholar
  56. 56.
    Corden LD, Mellerio JE, Gratian MJ, et al. Homozygous nonsense mutation in helix 2 of K14 causes severe recessive epidermolysis bullosa simplex. Hum Mutat 1998; 11: 279–285PubMedCrossRefGoogle Scholar
  57. 57.
    Rugg EL, McLean WHI, Lane EB, et al. A functional “knock-out” for human keratin 14. Genes Dev 1994; 8 (21): 2563–2573PubMedCrossRefGoogle Scholar
  58. 58.
    Jonkman MF, Heeres K, Pas HH, et al. Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex. J Invest Dermatol 1996; 107: 764–769PubMedCrossRefGoogle Scholar
  59. 59.
    Batta K, Rugg EL, Wilson NJ, et al. A keratin 14 ‘knockout’ mutation in recessive epidermolysis bullosa simplex resulting in less severe disease. Br J Dermatol 2000; 143 (3): 621–627PubMedCrossRefGoogle Scholar
  60. 60.
    Lloyd C, Yu QC, Cheng J, et al. The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14. J. Cell Biol 1995; 129 (5): 1329–1344PubMedCrossRefGoogle Scholar
  61. 61.
    Peters B, Kirfel J, Bussow H, et al. Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex. Mol Biol Cell 2001; 12 (6): 1775–1789PubMedGoogle Scholar
  62. 62.
    Anton-Lamprecht I. Genetically induced abnormalities of epidermal differentiation and ultrastructure in ichthyosis and epidermolysis: pathogenesis, heterogeneity, fetal manifestations, and prenatal diagnosis. J Invest Dermatol 1983; 81 (1 Suppl.): 149s–156sPubMedCrossRefGoogle Scholar
  63. 63.
    Ishida-Yamamoto A, McGrath JA, Judge MR, et al. Selective involvement of keratins K1 and K10 in the cytoskeletal abnormality of epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). J Invest Dermatol 1992; 99: 19–26PubMedCrossRefGoogle Scholar
  64. 64.
    Fuchs E, Esteves RA, Coulombe PA. Transgenic mice expressing a mutant K10 gene reveal the likely genetic basis for epidermolytic hyperkeratosis. Proc Natl Acad Sci USA 1992; 89: 6906–6910PubMedCrossRefGoogle Scholar
  65. 65.
    Bonifas JM, Bare JW, Chen MA, et al. Linkage of the epidermolytic hyperkeratosis phenotype and the region of the type II keratin gene cluster on chromosome 12. J Invest Dermatol 1992; 99: 524–527PubMedCrossRefGoogle Scholar
  66. 66.
    Compton JG, DiGiovanna JJ, Santucci SK, et al. Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q. Nature Genet 1992; 1: 301–305PubMedCrossRefGoogle Scholar
  67. 67.
    Cheng J, Syder AJ, Yu Q-C, et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell 1992; 70: 811–819PubMedCrossRefGoogle Scholar
  68. 68.
    Chipev CC, Korge BP, Markova N, et al. A leucine-proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 1992; 70: 821–828PubMedCrossRefGoogle Scholar
  69. 69.
    Rothnagel JA, Dominey AM, Dempsey LD, et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992; 257: 1128–1130PubMedCrossRefGoogle Scholar
  70. 70.
    Kremer H, Lavrijsen AP, McLean WH, et al. An atypical form of bullous congenital ichthyosiform erythroderma is caused by a mutation in the L12 linker region of keratin 1. J Invest Dermatol 1998; 111 (6): 1224–1226PubMedCrossRefGoogle Scholar
  71. 71.
    DiGiovanna JJ, Bale SJ. Epidermolytic hyperkeratosis: applied molecular genetics. J Invest Dermatol 1994; 102 (3): 390–394PubMedCrossRefGoogle Scholar
  72. 72.
    Yang JM, Nam K, Kim SW, et al. Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis. J Dermatol Sci 1999; 19 (2): 126–133PubMedCrossRefGoogle Scholar
  73. 73.
    Knapp AC, Franke WW, Heid H, et al. Cytokeratin no. 9, an epidermal type I keratin characteristic of a special program of keratinocyte differentiation displaying body site specificity. J Cell Biol 1986; 103: 657–667PubMedCrossRefGoogle Scholar
  74. 74.
    MoH I, Heid H, Franke WW, et al. Distribution of a special subset of keratinocytes characterized by the expression of cytokeratin 9 in adult and fetal human epidermis of various body sites. Differentiation 1987; 33: 254–265CrossRefGoogle Scholar
  75. 75.
    Paller AS, Syder AJ, Chan YM, et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 1994; 331 (21): 1408–1415PubMedCrossRefGoogle Scholar
  76. 76.
    Moss C, Jones DO, Blight A, et al. Birthmark due to cutaneous mosaicism for keratin 10 mutation [letter]. Lancet 1995; 345 (8949): 596PubMedCrossRefGoogle Scholar
  77. 77.
    Nomura K, Umeki K, Hatayama I, et al. Phenotypic heterogeneity in bullous congenital ichthyosiform erythroderma: possible somatic mosaicism for keratin gene mutation in the mildly affected mother of the proband. Arch Dermatol 2001; 137 (9): 1192–1195PubMedGoogle Scholar
  78. 78.
    Sahn EE, Weimer Jr CE, Garen PD. Annular epidermolytic ichthyosis: a unique phenotype. J Am Acad Dermatol 1992; 27 (2 Pt 2): 348–355PubMedCrossRefGoogle Scholar
  79. 79.
    Joh GY, Traupe H, Metze D, et al. A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol 1997; 108 (3): 357–361PubMedCrossRefGoogle Scholar
  80. 80.
    Suga Y, Duncan KO, Heald PW, et al. A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol 1998; III (6): 1220–1223CrossRefGoogle Scholar
  81. 81.
    Sybert VP, Francis JS, Corden LD, et al. Cyclic ichthyosis with epidermolytic hyperkeratosis: a phenotype conferred by mutations in the 2B domain of keratin K1. Am J Hum Genet 1999; 64 (3): 732–738PubMedCrossRefGoogle Scholar
  82. 82.
    Michael EJ, Schneiderman P, Grossman ME, et al. Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques resulting from a mutation in the keratin 1 gene. Exp Dermatol 1999; 8 (6): 501–503PubMedCrossRefGoogle Scholar
  83. 83.
    Siemens HW. Dichtung und Wahrheit über die die “Ichthyosis bullosa”, mit Bemerkungen zur Systematik der Epidermolysen. Arch Dermatol Syph (Berl) 1937; 175: 590–608Google Scholar
  84. 84.
    McLean WHI, Morley SM, Lane EB, et al. Ichthyosis bullosa of Siemens: a disease involving keratin 2e. J Invest Dermatol 1994; 103 (3): 277–281PubMedCrossRefGoogle Scholar
  85. 85.
    Collin C, MoH R, Kubicka S, et al. Characterization of human cytokeratin 2, an epidermal cytoskeleton protein synthesized late during differentiation. Exp Cell Res 1992; 202: 132–141PubMedCrossRefGoogle Scholar
  86. 86.
    Steijlen P, Kremer H, Vakilzadeh F, et al. Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa. J Invest Dermatol 1994; 103: 282–285PubMedCrossRefGoogle Scholar
  87. 87.
    Kremer H, Zeeuwen P, McLean WHI, et al. Ichthyosis bullosa of siemens is caused by mutations in the keratin 2e gene. J Invest Dermatol 1994; 103 (3): 286–289PubMedCrossRefGoogle Scholar
  88. 88.
    Rothnagel JA, Traupe H, Wojcik S, et al. Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet 1994; 7 (4): 485–490PubMedCrossRefGoogle Scholar
  89. 89.
    Gorlin RJ, Pindborg JJ, Cohen Jr MM. Syndromes of the Head and Neck. 2nd ed. New York: McGraw-Hill, 1976Google Scholar
  90. 90.
    Jadassohn J, Lewandowsky F. Pachyonychia congenita. Jacobs Ikonographia Dermatologica; vol 1. Berlin: Urban and Schwarzenberg, 1906Google Scholar
  91. 91.
    Jackson ADM, Lawler SD. Pachyonychia congenita: a report of six cases in one family. Ann Eugen 1951; 16: 142–146PubMedGoogle Scholar
  92. 92.
    McLean WHI, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 1995; 9: 273–278PubMedCrossRefGoogle Scholar
  93. 93.
    Smith FJD, Del Monaco M, Steijlen PM, et al. Novel proline substitution mutations in keratin 16 in two cases of pachyonychia conge nita type 1. Br J Dermatol 1999; 141: 1010–1016PubMedCrossRefGoogle Scholar
  94. 94.
    Bowden PE, Haley JL, Kansky A, et al. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet 1995; 10: 363–365PubMedCrossRefGoogle Scholar
  95. 95.
    Lin MT, Levy ML, Bowden PE, et al. Identification of sporadic mutations in the helix initiation motif of keratin 6 in two pachyonychia congenita patients: further evidence for a mutational hot spot. Exp Dermatol 1999; 8 (2): 115–119PubMedCrossRefGoogle Scholar
  96. 96.
    Terrinoni A, Smith FJD, Didona B, et al. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in thirteen cases of pachyonychia congenita. J Invest Dermatol 2001; 117 (6): 1391–1396PubMedCrossRefGoogle Scholar
  97. 97.
    Connors JB, Rahil AK, Smith FJD, et al. Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol 2001; 144 (5): 1058–1062PubMedCrossRefGoogle Scholar
  98. 98.
    Terrinoni A, Puddu P, Didona B, et al. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J Invest Dermatol 2000; 114 (6): 1136–1140PubMedCrossRefGoogle Scholar
  99. 99.
    Munro CS, Carter S, Bryce S, et al. A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21. J Med Genet 1994; 31: 675–678PubMedCrossRefGoogle Scholar
  100. 100.
    Troyanovsky SM, Guelstein VI, Tchipysheva TA, et al. Patterns of expression of K17 in human epithelia: dependency on cell position. J Cell Sci 1989; 93: 419–426PubMedGoogle Scholar
  101. 101.
    McGowan KM, Coulombe PA. Keratin 17 expression in the hard epithelial context of the hair and nail, and its relevance for the pachyonychia conge nita phenotype. J Invest Dermatol 2001; 114 (6): 1101–1107CrossRefGoogle Scholar
  102. 102.
    Smith FJD, Coleman CM, Bayoumy NM, et al. Novel keratin 17 mutations in pachyonychia congenita type 2. J Invest Dermatol 2001; 116 (5): 806–808PubMedCrossRefGoogle Scholar
  103. 103.
    Smith FJD, Jonkrnan MF, van Goor H, et al. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet 1998; 7 (7): 1143–1148PubMedCrossRefGoogle Scholar
  104. 104.
    Covello SP, Smith Fill, Sillevis Smitt JH, et al. Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol 1998; 139: 475–480PubMedCrossRefGoogle Scholar
  105. 105.
    Smith Fill, Corden ill, Rugg EL, et al. Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol 1997; 108 (2): 220–223PubMedCrossRefGoogle Scholar
  106. 106.
    Ratnavel RC, Griffiths W A. The inherited palmoplantar keratodermas. Br J Dermatol 1997; 137 (4): 485–490PubMedCrossRefGoogle Scholar
  107. 107.
    Vorner H. Zur Kenntniss des Keratoma hereditarium palmare et plantare. Arch Derm Syph 1901; 56: 3–31Google Scholar
  108. 108.
    Navsaria HA, Swensson O, Ratnavel RC, et al. ULtrastructural-changes resulting from keratin-9 gene-mutations in 2 families with epidermolytic palmoplantar keratoderma. J Invest Dermatol 1995; 104 (3): 425–429PubMedCrossRefGoogle Scholar
  109. 109.
    Reis A, Kuster W, Eckardt R, et al. Mapping of a gene for epidermolytic palmoplantar keratoderma to the region of acidic keratin gene cluster at 17q12-q21. Hum Genet 1992; 90: 113–116PubMedCrossRefGoogle Scholar
  110. 110.
    Reis A, Hennies H-C, Langbein L, et al. Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). Nat Genet 1994; 6: 174–179PubMedCrossRefGoogle Scholar
  111. 111.
    Coleman CM, Munro CS, Smith Fill, et al. Epidermolytic palmoplantar keratoderma due to a novel type of keratin mutation, a 3 bp insertion in the keratin 9 helix termination motif. Br J Dermatol 1999; 140: 486–490PubMedCrossRefGoogle Scholar
  112. 112.
    Hatsell SJ, Eady RA, Wennerstrand L, et al. Novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol 2001; 116 (4): 606–609PubMedCrossRefGoogle Scholar
  113. 113.
    Kimonis V, DiGiovanna JJ, Yang J-M, et al. A mutation in the VI end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J Invest Dermatol 1994; 103 (6): 764–769PubMedCrossRefGoogle Scholar
  114. 114.
    Sprecher E, Ishida-Yamamoto A, Becker OM, et al. Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix. J Invest Derrnatol 2001; 116 (4): 511–519CrossRefGoogle Scholar
  115. 115.
    Bonifas JM, Bare JW, Chen MA, et al. Evidence against keratin gene mutations in a family with ichthyosis hystrix Curth-Macklin. J Invest Dermatol 1993; 101 (6): 890–891PubMedCrossRefGoogle Scholar
  116. 116.
    Shamsher MK, Navsaria HA, Stevens HP, et al. Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in 2 families. Hum Mol Genet 1995; 4 (10): 1875–1881PubMedCrossRefGoogle Scholar
  117. 117.
    Smith FJD, Fisher MP, Healy E, et al. Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp Dermatol 2000; 9: 170–177PubMedCrossRefGoogle Scholar
  118. 118.
    Jorgenson RJ, Levin S. White sponge nevus. Arch Dermatol 1981; 117: 73–76PubMedCrossRefGoogle Scholar
  119. 119.
    McGinnis JP, Turner JE. Ultrastructure of the white sponge nevus. Oral Surg 1975; 40 (5): 644–651CrossRefGoogle Scholar
  120. 120.
    Frithiof L, Banoczy J. White sponge nevus (leukoedema exfoliativum mucosae oris): ultrastructural observations. Oral Surg 1976; 41 (5): 607–622PubMedCrossRefGoogle Scholar
  121. 121.
    Rugg EL, McLean WHI, Allison WE, et al. A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Nat Genet 1995; 11: 450–452PubMedCrossRefGoogle Scholar
  122. 122.
    Richard G, DeLaurenzi V, DiDona B, et al. Keratin-13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus. Nat Genet 1995; 11 (4): 453–455PubMedCrossRefGoogle Scholar
  123. 123.
    Terrinoni A, Candi E, Oddi S, et al. A glutamine insertion in the 1 A alpha helical domain of the keratin 4 gene in a familial case of white sponge nevus. J Invest Derrnatol 2000; 114 (2): 388–391CrossRefGoogle Scholar
  124. 124.
    Terrinoni A, Rugg EL, Lane EB, et al. A novel mutation in the keratin 13 gene causing oral white sponge nevus. J Dent Res 2001; 80 (3): 919–923PubMedCrossRefGoogle Scholar
  125. 125.
    Rugg E, Magee G, Wilson N, et al. Identification of two novel mutations in keratin 13 as the cause of white sponge naevus. Oral Dis 1999; 5 (4): 321–324PubMedCrossRefGoogle Scholar
  126. 126.
    Munro CS. The clinical consequences of keratin gene defects. Dermatol Practice 1998; 6 (6): 8–11Google Scholar
  127. 127.
    Meesmann A, Wilke F. Klinische und anatomische Untersuchungen ueber eine bisher unbekannte, dominant vererbte Epitheldystrophie der Hornhaut. Klin Mbl Augenheilk 1939; 103: 361–391Google Scholar
  128. 128.
    Tremblay M, Dube I. Meesmann’s corneal dystrophy: ultrastructural features. Can J Ophthalmol 1982; 17 (1): 24–28PubMedGoogle Scholar
  129. 129.
    Liu CY, Zhu G, Westerhausen-Larson A, et al. Cornea-specific expression of K12 keratin during mouse development. Curr Eye Res 1993; 12 (11): 963–974PubMedCrossRefGoogle Scholar
  130. 130.
    Kao WW-Y, Liu C-Y, Converse RL, et al. Keratin 12 deficient mice have fragile corneal epithelia. Invest Ophthalmol Vis Sci 1996; 37: 2572–2584PubMedGoogle Scholar
  131. 131.
    Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratins K3 or K12 cause Meesmann’s corneal dystrophy. Nat Genet 1997; 16: 184–187PubMedCrossRefGoogle Scholar
  132. 132.
    Nishida K, Honma Y, Dota A, et al. Isolation and chromosomal localization of a cornea-specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy. Am J Hum Genet 1997; 61 (6): 1268–1275PubMedCrossRefGoogle Scholar
  133. 133.
    Coleman CM, Hannush S, Covello SP, et al. A novel mutation in the helix termination motif of keratin K12 in a US family with Meesmann corneal dystrophy. Am J Ophthalmol 1999; 128 (6): 687–691PubMedCrossRefGoogle Scholar
  134. 134.
    Corden LD, Swensson O, Swensson B, et al. Molecular genetics of Meesmann’s corneal dystrophy: ancestral and novel mutations in keratin 12 (K12) and complete sequence of the human KRT12 gene. Exp Eye Res 2000; 70 (1): 41–49PubMedCrossRefGoogle Scholar
  135. 135.
    Corden LD, Swensson O, Swensson B, et al. A novel keratin 12 mutation in a German kindred with Meesmann’s corneal dystrophy. Br J Ophthalmol 2000; 84 (5): 527–530PubMedCrossRefGoogle Scholar
  136. 136.
    Ku NO, Michie S, Oshima RG, et al. Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant. J Cell Biol 1995; 131 (5): 1303–1314PubMedCrossRefGoogle Scholar
  137. 137.
    Ku NO, Wright TL, Terrault NA, et al. Mutation of human keratin 18 in association with cryptogenic cirrhosis. J Din Invest 1997; 99 (1): 19–23Google Scholar
  138. 138.
    Ku NO, Gish R, Wright TL, et al. Keratin 8 mutations in patients with cryptogenic liver disease. N Engl J Med 2001; 344 (21): 1580–1587PubMedCrossRefGoogle Scholar
  139. 139.
    Ito M, Hashimoto K, Katsuumi K, et al. Pathogenesis of monilethrix: computer stereography and electron microscopy. J Invest Dermatol 1990; 95 (2): 186–194PubMedCrossRefGoogle Scholar
  140. 140.
    Healy E, Holmes SC, Belgaid CE, et al. A gene for monilethrix is closely linked to the type II keratin gene cluster at 12gB. Hum Mol Genet 1995; 4 (12): 2399–2402PubMedCrossRefGoogle Scholar
  141. 141.
    Stevens HP, Kelsell DP, Bryant SP, et al. Linkage of monilethrix to the trichocyte and epithelial keratin gene cluster on 12q11-q13. J Invest Dermatol 1996; 106 (4): 795–797PubMedCrossRefGoogle Scholar
  142. 142.
    Winter H, Rogers MA, Langbein L, et al. Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet 1997; 16 (4): 372–374PubMedCrossRefGoogle Scholar
  143. 143.
    Winter H, Rogers MA, Gebhardt M, et al. A new mutation in the type II hair cortex keratin hHbl involved in the inherited hair disorder monilethrix. Hum Genet 1997; 101 (2): 165–169PubMedCrossRefGoogle Scholar
  144. 144.
    Takahashi K, Paladini RD, Coulombe PA. Cloning and characterization of multiple human genes and cDN As encoding highly related type II keratin 6 isoforms. J Biol Chem 1995; 270 (31): 18581–18592PubMedCrossRefGoogle Scholar
  145. 145.
    Savtchenko ES, Freedberg IM, Choi I-Y, et al. Inactivation of human keratin genes: the spectrum of mutations in the sequence of an acidic keratin pseudogene. Mol Biol Evol 1988; 5 (1): 97–108PubMedGoogle Scholar
  146. 146.
    Troyanovsky SM, Leube RE, Franke WW. Characterization of the human gene encoding cytokeratin 17 and its expression pattern. Eur J Cell Biol 1992; 59 (1): 127–137PubMedGoogle Scholar
  147. 147.
    Ruud P, Fodstad O, Hovig E. Identification of a novel cytokeratin 19 pseudogene that may interfere with reverse transcriptase-polymerase chain reaction assays used to detect micro metastatic tumor cells. Int J Cancer 1999; 80 (1): 119–125PubMedCrossRefGoogle Scholar
  148. 148.
    RayChaudhury A, Marchuk D, Lindhurst M, et al. Three tightly linked genes encoding human type I keratins: conservation of sequence in the 5’-untranslated leader and 5’-upstream regions of coexpressed keratin genes. Mol Cell Biol 1986; 6: 539–548PubMedGoogle Scholar
  149. 149.
    Paladini RD, Takahashi K, Gant TM, et al. cDNA cloning and bacterial expression of the human type I keratin 16. Biochem Biophys Res Commun 1995; 215 (2): 517–523PubMedCrossRefGoogle Scholar
  150. 150.
    Smith FJD, McKusick V A, Nielsen K, et al. Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1. Prenat Diagn 1999; 19: 941–946PubMedCrossRefGoogle Scholar
  151. 151.
    Smith FJD, McKenna KE, Irvine AD, et al. A mutation detection strategy for the human K6A gene and novel mutations in two cases of pachyonychia congenita type 1. Exp Dermatol 1999; 8: 109–114PubMedCrossRefGoogle Scholar
  152. 152.
    McLean Will, Pulkkinen L, Smith FJD, et al. Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organisation. Genes Dev 1996; 10: 1724–1735PubMedCrossRefGoogle Scholar
  153. 153.
    Uitto I, Pulkkinen L, Smith FJD, et al. Plectin and human genetic disorders of skin and muscle: the paradigm of epidermolysis bullosa with muscular dystrophy. Exp Dermatol 1996; 5: 237–246PubMedCrossRefGoogle Scholar
  154. 154.
    McGrath JA, McMillan JR, Shemanko CS, et al. Mutations in the plakophilin 1 gene can result in ectodermal dysplasia/skin fragility syndrome. Nat Genet 1997; 17 (2): 240–244PubMedCrossRefGoogle Scholar
  155. 155.
    Cao T, Longley MA, Wang XJ, et al. An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy. J Cell Biol 2001; 152 (3): 651–656PubMedCrossRefGoogle Scholar
  156. 156.
    Rothnagel JA, Longley MA, Holder RA, et al. Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene sequencing. J Invest Dermatol 1994; 102 (1): 13–16PubMedCrossRefGoogle Scholar
  157. 157.
    Rothnagel JA, Lin MT, Longley MA, et al. Prenatal diagnosis for keratin mutations to exclude transmission of epidermolytic hyperkeratosis. Prenat Diagn 1998; 18 (8): 826–830PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2003

Authors and Affiliations

  1. 1.Epithelial Genetics Group, Human Genetics UnitUniversity of Dundee, Ninewells Hospital and Medical SchoolDundeeUK

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