Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

The molecular basis of human keratin disorders

  • 614 Accesses

  • 37 Citations

Abstract

Keratins are cytoskeletal proteins that provide structural support to epithelial cells and tissues. Perturbation causes cell and tissue fragility and accounts for a large number of genetic disorders in humans. In humans, 54 functional keratin genes exist and 21 different keratin genes including hair keratins and hair follicle-specific epithelial keratins have been associated with hereditary disorders. Moreover, keratins have been implicated in more complex traits such as liver disease and inflammatory bowel disease. Understanding the molecular basis of keratin disorders has been the basis for improved diagnosis with prognostic implications, genetic counseling and prenatal testing for severe disorders. Besides their mechanical role, keratins have newly identified functions in apoptosis, cell growth, tissue polarity, wound healing and tissue remodeling. Improved understanding of the regulatory functions of keratins may offer novel approaches to overcome current treatment limitations.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell DP (2001) Review article: the genetics of inflammatory bowel disease. Aliment Pharmacol Ther 15:731–748

  2. Anton-Lamprecht I (1994) Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis. J Invest Dermatol 103:6S–12S

  3. Arin MJ, Longley MA, Anton-Lamprecht I, Kurze G, Huber M, Hohl D, Rothnagel JA, Roop DR (1999) A novel substitution in keratin 10 in epidermolytic hyperkeratosis. J Invest Dermatol 112:506–508

  4. Arin MJ, Longley MA, Wang XJ, Roop DR (2001) Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders. J Cell Biol 152:645–649

  5. Barak V, Goike H, Panaretakis KW, Einarsson R (2004) Clinical utility of cytokeratins as tumor markers. Clin Biochem 37:529–540

  6. Betz RC, Planko L, Eigelshoven S, Hanneken S, Pasternack SM, Bussow H, Van Den Bogaert K, Wenzel J, Braun-Falco M, Rutten A, Rogers MA, Ruzicka T, Nothen MM, Magin TM, Kruse R (2006) Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet 78:510–519

  7. Bonifas JM, Rothman AL, Epstein EH Jr (1991) Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254:1202–1205

  8. Bonifas JM, Bare JW, Chen MA, Ranki A, Neimi KM, Epstein EH Jr (1993) Evidence against keratin gene mutations in a family with ichthyosis hystrix Curth-Macklin. J Invest Dermatol 101:890–891

  9. Bowden PE, Haley JL, Kansky A, Rothnagel JA, Jones DO, Turner RJ (1995) Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet 10:363–365

  10. Braun-Falco M, Volgger W, Borelli S, Ring J, Disch R (2001) Galli-Galli disease: an unrecognized entity or an acantholytic variant of Dowling-Degos disease? J Am Acad Dermatol 45:760–763

  11. Buning C, Halangk J, Dignass A, Ockenga J, Deindl P, Nickel R, Genschel J, Landt O, Lochs H, Schmidt H, Witt H (2004) Keratin 8 Y54H and G62C mutations are not associated with inflammatory bowel disease. Dig Liver Dis 36:388–391

  12. Candi E, Tarcsa E, Digiovanna JJ, Compton JG, Elias PM, Marekov LN, Steinert PM (1998) A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases. Proc Natl Acad Sci U S A 95:2067–2072

  13. Cao T, Longley MA, Wang XJ, Roop DR (2001) An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy. J Cell Biol 152:651–656

  14. Chassaing N, Kanitakis J, Sportich S, Cordier-Alex MP, Titeux M, Calvas P, Claudy A, Berbis P, Hovnanian A (2006) Generalized epidermolytic hyperkeratosis in two unrelated children from parents with localized linear form, and prenatal diagnosis. J Invest Dermatol 126:2715–2717

  15. Cheng J, Syder AJ, Yu QC, Letai A, Paller AS, Fuchs E (1992) The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell 70:811–819

  16. Chipev CC, Korge BP, Markova N, Bale SJ, Di Giovanna JJ, Compton JG, Steinert PM (1992) A leucine–proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 70:821–828

  17. Coleman CM, Munro CS, Smith FJ, Uitto J, McLean WH (1999) 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 140:486–490

  18. Connors JB, Rahil AK, Smith FJ, McLean WH, Milstone LM (2001) Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol 144:1058–1062

  19. Coulombe PA, Hutton ME, Letai A, Hebert A, Paller AS, Fuchs E (1991) Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 66:1301–1311

  20. Covello SP, Smith FJ, Sillevis Smitt JH, Paller AS, Munro CS, Jonkman MF, Uitto J, McLean WH (1998) Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol 139:475–480

  21. Cummins RE, Klingberg S, Wesley J, Rogers M, Zhao Y, Murrell DF (2001) Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes. J Invest Dermatol 117:1103–1107

  22. D’Alessandro M, Morley SM, Ogden PH, Liovic M, Porter RM, Lane EB (2004) Functional improvement of mutant keratin cells on addition of desmin: an alternative approach to gene therapy for dominant diseases. Gene Ther 11:1290–1295

  23. Dabbs DJ, Chivukula M, Carter G, Bhargava R (2006) Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile. Mod Pathol 19:1506–1511

  24. De Berker D, Wojnarowska F, Sviland L, Westgate GE, Dawber RP, Leigh IM (2000) Keratin expression in the normal nail unit: markers of regional differentiation. Br J Dermatol 142:89–96

  25. DiGiovanna JJ, Bale SJ (1994) Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol 130:1026–1035

  26. Dykxhoorn DM, Lieberman J (2006) Knocking down disease with siRNAs. Cell 126:231–235

  27. Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, McGrath JA, Mellerio JE, Murrell DF, Shimizu H, Uitto J, Vahlquist A, Woodley D, Zambruno G (2008) The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 58:931–950

  28. Frithiof L, Banoczy J (1976) White sponge nevus (leukoedema exfoliativum mucosae oris): ultrastructural observations. Oral Surg Oral Med Oral Pathol 41:607–622

  29. Grimberg G, Hausser I, Muller FB, Wodecki K, Schaffrath C, Krieg T, Oji V, Traupe H, Arin MJ (2009) Novel and recurrent mutations in the 1B domain of keratin 1 in palmoplantar keratoderma with tonotubules. Br J Dermatol 160:446–449

  30. Gu LH, Coulombe PA (2007) Keratin function in skin epithelia: a broadening palette with surprising shades. Curr Opin Cell Biol 19:13–23

  31. Gu LH, Kim SC, Ichiki Y, Park J, Nagai M, Kitajima Y (2003) A usual frameshift and delayed termination codon mutation in keratin 5 causes a novel type of epidermolysis bullosa simplex with migratory circinate erythema. J Invest Dermatol 121:482–485

  32. Harel A, Bergman R, Indelman M, Sprecher E (2006) Epidermolysis bullosa simplex with mottled pigmentation resulting from a recurrent mutation in KRT14. J Invest Dermatol 126:1654–1657

  33. Haruna K, Suga Y, Mizuno Y, Hasegawa T, Kourou K, Matsuba S, Muramatsu S, Ikeda S (2007) R156C mutation of keratin 10 causes mild form of epidermolytic hyperkeratosis. J Dermatol 34:545–548

  34. Has C, Chang YR, Volz A, Hoeping D, Kohlhase J, Bruckner-Tuderman L (2006) Novel keratin 14 mutations in patients with severe recessive epidermolysis bullosa simplex. J Invest Dermatol 126:1912–1914

  35. Hatsell SJ, Eady RA, Wennerstrand L, Dopping-Hepenstal P, Leigh IM, Munro C, Kelsell DP (2001) Novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol 116:606–609

  36. Hengge UR (2006) Gene therapy progress and prospects: the skin–easily accessible, but still far away. Gene Ther 13:1555–1563

  37. Hengge UR, Chan EF, Foster RA, Walker PS, Vogel JC (1995) Cytokine gene expression in epidermis with biological effects following injection of naked DNA. Nat Genet 10:161–166

  38. Hesse M, Berg T, Wiedenmann B, Spengler U, Woitas RP, Magin TM (2004) A frequent keratin 8 p.L227L polymorphism, but no point mutations in keratin 8 and 18 genes, in patients with various liver disorders. J Med Genet 41:e42

  39. Hesse M, Grund C, Herrmann H, Brohl D, Franz T, Omary MB, Magin TM (2007) A mutation of keratin 18 within the coil 1A consensus motif causes widespread keratin aggregation but cell type-restricted lethality in mice. Exp Cell Res 313:3127–3140

  40. Horev L, Glaser B, Metzker A, Ben-Amitai D, Vardy D, Zlotogorski A (2000) Monilethrix: mutational hotspot in the helix termination motif of the human hair basic keratin 6. Hum Hered 50:325–330

  41. Horiguchi Y, Sawamura D, Mori R, Nakamura H, Takahashi K, Shimizu H (2005) Clinical heterogeneity of 1649delG mutation in the tail domain of keratin 5: a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol 125:83–85

  42. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603

  43. Hutton E, Paladini RD, Yu QC, Yen M, Coulombe PA, Fuchs E (1998) Functional differences between keratins of stratified and simple epithelia. J Cell Biol 143:487–499

  44. Irvine AD, McLean WH (1999) Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation. Br J Dermatol 140:815–828

  45. Irvine AD, Corden LD, Swensson O, Swensson B, Moore JE, Frazer DG, Smith FJ, Knowlton RG, Christophers E, Rochels R, Uitto J, McLean WH (1997a) Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann’s corneal dystrophy. Nat Genet 16:184–187

  46. Irvine AD, McKenna KE, Jenkinson H, Hughes AE (1997b) A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol 108:809–810

  47. Irvine AD, Rugg EL, Lane EB, Hoare S, Peret C, Hughes AE, Heagerty AH (2001) Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol 144:40–45

  48. Ishida-Yamamoto A, Tanaka H, Nakane H, Takahashi H, Iizuka H (1998) Inherited disorders of epidermal keratinization. J Dermatol Sci 18:139–154

  49. Itin PH, Fistarol SK (2005) Palmoplantar keratodermas. Clin Dermatol 23:15–22

  50. Izawa I, Inagaki M (2006) Regulatory mechanisms and functions of intermediate filaments: a study using site- and phosphorylation state-specific antibodies. Cancer Sci 97:167–174

  51. Joh GY, Traupe H, Metze D, Nashan D, Huber M, Hohl D, Longley MA, Rothnagel JA, Roop DR (1997) A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol 108:357–361

  52. Jonkman MF, Heeres K, Pas HH, van Luyn MJ, Elema JD, Corden LD, Smith FJ, McLean WH, Ramaekers FC, Burton M, Scheffer H (1996) Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex. J Invest Dermatol 107:764–769

  53. Khavari PA, Rollman O, Vahlquist A (2002) Cutaneous gene transfer for skin and systemic diseases. J Intern Med 252:1–10

  54. Kim S, Coulombe PA (2007) Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes Dev 21:1581–1597

  55. Kimonis V, DiGiovanna JJ, Yang JM, Doyle SZ, Bale SJ, Compton JG (1994) A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J Invest Dermatol 103:764–769

  56. Kirfel J, Peters B, Grund C, Reifenberg K, Magin TM (2002) Ectopic expression of desmin in the epidermis of transgenic mice permits development of a normal epidermis. Differentiation 70:56–68

  57. Kirfel J, Magin TM, Reichelt J (2003) Keratins: a structural scaffold with emerging functions. Cell Mol Life Sci 60:56–71

  58. Kon A, Ito N, Kudo Y, Nomura K, Yoneda K, Hanada K, Hashimoto I, Takagaki K (2006) L457F missense mutation within the 2B rod domain of keratin 9 in a Japanese family with epidermolytic palmoplantar keratoderma. Br J Dermatol 155:624–626

  59. Ku NO, Omary MB (2006) A disease- and phosphorylation-related nonmechanical function for keratin 8. J Cell Biol 174:115–125

  60. Ku NO, Lim JK, Krams SM, Esquivel CO, Keeffe EB, Wright TL, Parry DA, Omary MB (2005) Keratins as susceptibility genes for end-stage liver disease. Gastroenterology 129:885–893

  61. Ku NO, Strnad P, Zhong BH, Tao GZ, Omary MB (2007) Keratins let liver live: mutations predispose to liver disease and crosslinking generates Mallory-Denk bodies. Hepatology 46:1639–1649

  62. Kuster W, Zehender D, Mensing H, Hennies HC, Reis A (1995) Vorner keratosis palmoplantaris diffusa. Clinical, formal genetic and molecular biology studies of 22 families. Hautarzt 46:705–710

  63. Kuster W, Reis A, Hennies HC (2002) Epidermolytic palmoplantar keratoderma of Vorner: re-evaluation of Vorner’s original family and identification of a novel keratin 9 mutation. Arch Dermatol Res 294:268–272

  64. Lane EB, McLean WH (2004) Keratins and skin disorders. J Pathol 204:355–366

  65. Lane EB, Rugg EL, Navsaria H, Leigh IM, Heagerty AH, Ishida-Yamamoto A, Eady RA (1992) A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature 356:244–246

  66. Langbein L, Schweizer J (2005) Keratins of the human hair follicle. Int Rev Cytol 243:1–78

  67. Leachman SA, Hickerson RP, Hull PR, Smith FJ, Milstone LM, Lane EB, Bale SJ, Roop DR, McLean WH, Kaspar RL (2008) Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita. J Dermatol Sci 51:151–157

  68. Lee P, Gelbart T, West C, Halloran C, Beutler E (2002) Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol Dis 29:471–487

  69. Liao H, Zhao Y, Baty DU, McGrath JA, Mellerio JE, McLean WH (2007) A heterozygous frameshift mutation in the V1 domain of keratin 5 in a family with Dowling-Degos disease. J Invest Dermatol 127:298–300

  70. Lu H, Chen J, Planko L, Zigrino P, Klein-Hitpass L, Magin TM (2007) Induction of inflammatory cytokines by a keratin mutation and their repression by a small molecule in a mouse model for EBS. J Invest Dermatol 127:2781–2789

  71. Lugassy J, Itin P, Ishida-Yamamoto A, Holland K, Huson S, Geiger D, Hennies HC, Indelman M, Bercovich D, Uitto J, Bergman R, McGrath JA, Richard G, Sprecher E (2006) Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet 79:724–730

  72. Lugassy J, McGrath JA, Itin P, Shemer R, Verbov J, Murphy HR, Ishida-Yamamoto A, Digiovanna JJ, Bercovich D, Karin N, Vitenshtein A, Uitto J, Bergman R, Richard G, Sprecher E (2008) KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol 128:1517–1524

  73. Magin TM, Schroder R, Leitgeb S, Wanninger F, Zatloukal K, Grund C, Melton DW (1998) Lessons from keratin 18 knockout mice: formation of novel keratin filaments, secondary loss of keratin 7 and accumulation of liver-specific keratin 8-positive aggregates. J Cell Biol 140:1441–1451

  74. Magin TM, Kaiser HW, Leitgeb S, Grund C, Leigh IM, Morley SM, Lane EB (2000) Supplementation of a mutant keratin by stable expression of desmin in cultured human EBS keratinocytes. J Cell Sci 113(Pt 23):4231–4239

  75. Magin TM, Vijayaraj P, Leube RE (2007) Structural and regulatory functions of keratins. Exp Cell Res 313:2021–2032

  76. Marceau N, Schutte B, Gilbert S, Loranger A, Henfling ME, Broers JL, Mathew J, Ramaekers FC (2007) Dual roles of intermediate filaments in apoptosis. Exp Cell Res 313:2265–2281

  77. Margolis SS, Perry JA, Forester CM, Nutt LK, Guo Y, Jardim MJ, Thomenius MJ, Freel CD, Darbandi R, Ahn JH, Arroyo JD, Wang XF, Shenolikar S, Nairn AC, Dunphy WG, Hahn WC, Virshup DM, Kornbluth S (2006) Role for the PP2A/B56delta phosphatase in regulating 14–3-3 release from Cdc25 to control mitosis. Cell 127:759–773

  78. McLean WH, Rugg EL, Lunny DP, Morley SM, Lane EB, Swensson O, Dopping-Hepenstal PJ, Griffiths WA, Eady RA, Higgins C et al (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273–278

  79. McLean WH, Morley SM, Higgins C, Bowden PE, White M, Leigh IM, Lane EB (1999) Novel and recurrent mutations in keratin 10 causing bullous congenital ichthyosiform erythroderma. Exp Dermatol 8:120–123

  80. McLean WH, Smith FJ, Cassidy AJ (2005) Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database. J Investig Dermatol Symp Proc 10:31–36

  81. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R (1982) The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31:11–24

  82. Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129:705–733

  83. Moss C, Jones DO, Blight A, Bowden PE (1995) Birthmark due to cutaneous mosaicism for keratin 10 mutation. Lancet 345:596

  84. Muller FB, Huber M, Kinaciyan T, Hausser I, Schaffrath C, Krieg T, Hohl D, Korge BP, Arin MJ (2006a) A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. Hum Mol Genet 15:1133–1141

  85. Muller FB, Kuster W, Wodecki K, Almeida H Jr, Bruckner-Tuderman L, Krieg T, Korge BP, Arin MJ (2006b) Novel and recurrent mutations in keratin KRT5 and KRT14 genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly. Hum Mutat 27:719–720

  86. Naeem M, Wajid M, Lee K, Leal SM, Ahmad W (2006) A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type. J Med Genet 43:274–279

  87. Nagao-Watanabe M, Fukao T, Matsui E, Kaneko H, Inoue R, Kawamoto N, Kasahara K, Nagai M, Ichiki Y, Kitajima Y, Kondo N (2004) Identification of somatic and germline mosaicism for a keratin 5 mutation in epidermolysis bullosa simplex in a family of which the proband was previously regarded as a sporadic case. Clin Genet 66:236–238

  88. Nielsen K, Orntoft T, Hjortdal J, Rasmussen T, Ehlers N (2008) A novel mutation as the basis for asymptomatic meesmann dystrophy in a Danish family. Cornea 27:100–102

  89. Niemi KM, Virtanen I, Kanerva L, Muttilainen M (1990) Altered keratin expression in ichthyosis hystrix Curth-Macklin. A light and electron microscopic study. Arch Dermatol Res 282:227–233

  90. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

  91. Omary MB, Ku NO, Tao GZ, Toivola DM, Liao J (2006) “Heads and tails” of intermediate filament phosphorylation: multiple sites and functional insights. Trends Biochem Sci 31:383–394

  92. Owens DW, Wilson NJ, Hill AJ, Rugg EL, Porter RM, Hutcheson AM, Quinlan RA, van Heel D, Parkes M, Jewell DP, Campbell SS, Ghosh S, Satsangi J, Lane EB (2004) Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients. J Cell Sci 117:1989–1999

  93. Paller AS, Syder AJ, Chan YM, Yu QC, Hutton E, Tadini G, Fuchs E (1994) Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 331:1408–1415

  94. Parkes M, Barmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH (2000) The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Hum Genet 67:1605–1610

  95. Parry DA (1996) Hard alpha-keratin intermediate filaments: an alternative interpretation of the low-angle equatorial X-ray diffraction pattern, and the axial disposition of putative disulphide bonds in the intra- and inter-protofilamentous networks. Int J Biol Macromol 19:45–50

  96. Porter RM, Lane EB (2003) Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet 19:278–285

  97. Reddy BS, Thadeus J, Kumar SK, Jaishanker T, Garg BR (1997) Generalized epidermolytic hyperkeratosis in a child born to a parent with systematized epidermolytic linear epidermal nevus. Int J Dermatol 36:198–200

  98. Richard G, De Laurenzi V, Didona B, Bale SJ, Compton JG (1995) Keratin 13 point mutation underlies the hereditary mucosal epithelial disorder white sponge nevus. Nat Genet 11:453–455

  99. Richardson ES, Lee JB, Hyde PH, Richard G (2006) A novel mutation and large size polymorphism affecting the V2 domain of keratin 1 in an African-American family with severe, diffuse palmoplantar keratoderma of the ichthyosis hystrix Curth-Macklin type. J Invest Dermatol 126:79–84

  100. Roop D (1995) Defects in the barrier. Science 267:474–475

  101. Rothnagel JA, Dominey AM, Dempsey LD, Longley MA, Greenhalgh DA, Gagne TA, Huber M, Frenk E, Hohl D, Roop DR (1992) Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 257:1128–1130

  102. Rothnagel JA, Traupe H, Wojcik S, Huber M, Hohl D, Pittelkow MR, Saeki H, Ishibashi Y, Roop DR (1994) Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet 7:485–490

  103. Rugg EL, McLean WH, Lane EB, Pitera R, McMillan JR, Dopping-Hepenstal PJ, Navsaria HA, Leigh IM, Eady RA (1994) A functional “knockout” of human keratin 14. Genes Dev 8:2563–2573

  104. Rugg EL, McLean WH, Allison WE, Lunny DP, Macleod RI, Felix DH, Lane EB, Munro CS (1995) A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Nat Genet 11:450–452

  105. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 14:199–202

  106. Sawamura D, Akiyama M, Shimizu H (2002) Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy. Clin Exp Dermatol 27:480–484

  107. Schaffer JV, Bazzi H, Vitebsky A, Witkiewicz A, Kovich OI, Kamino H, Shapiro LS, Amin SP, Orlow SJ, Christiano AM (2006) Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol 126:1286–1291

  108. Schmitt AM, Anlauf M, Rousson V, Schmid S, Kofler A, Riniker F, Bauersfeld J, Barghorn A, Probst-Hensch NM, Moch H, Heitz PU, Kloeppel G, Komminoth P, Perren A (2007) WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors. Am J Surg Pathol 31:1677–1682

  109. Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, Maltais L, Omary MB, Parry DA, Rogers MA, Wright MW (2006) New consensus nomenclature for mammalian keratins. J Cell Biol 174:169–174

  110. Schweizer J, Langbein L, Rogers MA, Winter H (2007) Hair follicle-specific keratins and their diseases. Exp Cell Res 313:2010–2020

  111. Shamsher MK, Navsaria HA, Stevens HP, Ratnavel RC, Purkis PE, Kelsell DP, McLean WH, Cook LJ, Griffiths WA, Gschmeissner S et al (1995) Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. Hum Mol Genet 4:1875–1881

  112. Sheth N, Greenblatt D, McGrath JA (2007) New KRT10 gene mutation underlying the annular variant of bullous congenital ichthyosiform erythroderma with clinical worsening during pregnancy. Br J Dermatol 157:602–604

  113. Shimomura Y, Sakamoto F, Kariya N, Matsunaga K, Ito M (2006) Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J Invest Dermatol 126:1281–1285

  114. Smith FJ (2004) Nail that mutation-keratin 17 defect in late-onset pachyonychia. J Invest Dermatol 122:x–xi

  115. Smith FJ, Corden LD, Rugg EL, Ratnavel R, Leigh IM, Moss C, Tidman MJ, Hohl D, Huber M, Kunkeler L, Munro CS, Lane EB, McLean WH (1997) Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol 108:220–223

  116. Smith FJ, Fisher MP, Healy E, Rees JL, Bonifas JM, Epstein EH Jr, Tan EM, Uitto J, McLean WH (2000) Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp Dermatol 9:170–177

  117. Sprecher E, Ishida-Yamamoto A, Becker OM, Marekov L, Miller CJ, Steinert PM, Neldner K, Richard G (2001) Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix. J Invest Dermatol 116:511–519

  118. Sprecher E, Indelman M, Khamaysi Z, Lugassy J, Petronius D, Bergman R (2007) Galli-Galli disease is an acantholytic variant of Dowling-Degos disease. Br J Dermatol 156:572–574

  119. Steinert PM (1993) Structure, function, and dynamics of keratin intermediate filaments. J Invest Dermatol 100:729–734

  120. Steinert PM, North AC, Parry DA (1994) Structural features of keratin intermediate filaments. J Invest Dermatol 103:19S–24S

  121. Strnad P, Lienau TC, Tao GZ, Ku NO, Magin TM, Omary MB (2006) Denaturing temperature selection may underestimate keratin mutation detection by DHPLC. Hum Mutat 27:444–452

  122. Strnad P, Stumptner C, Zatloukal K, Denk H (2008) Intermediate filament cytoskeleton of the liver in health and disease. Histochem Cell Biol 129:735–749

  123. Suga Y, Duncan KO, Heald PW, Roop DR (1998) A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol 111:1220–1223

  124. Sybert VP (1997) Genetic skin disorders. Oxford monographs on medical genetics, vol 33. Oxford University Press, New York

  125. Sybert VP, Francis JS, Corden LD, Smith LT, Weaver M, Stephens K, McLean WH (1999) Cyclic ichthyosis with epidermolytic hyperkeratosis: a phenotype conferred by mutations in the 2B domain of keratin K1. Am J Hum Genet 64:732–738

  126. Syder AJ, Yu QC, Paller AS, Giudice G, Pearson R, Fuchs E (1994) Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between location and disease severity. J Clin Invest 93:1533–1542

  127. Tal O, Bergman R, Alcalay J, Indelman M, Sprecher E (2005) Epidermolytic hyperkeratosis type PS-1 caused by aberrant splicing of KRT1. Clin Exp Dermatol 30:64–67

  128. Tao GZ, Strnad P, Zhou Q, Kamal A, Zhang L, Madani ND, Kugathasan S, Brant SR, Cho JH, Omary MB, Duerr RH (2007) Analysis of keratin polypeptides 8 and 19 variants in inflammatory bowel disease. Clin Gastroenterol Hepatol 5:857–864

  129. Terrinoni A, Puddu P, Didona B, De Laurenzi V, Candi E, Smith FJ, McLean WH, Melino G (2000) A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J Invest Dermatol 114:1136–1140

  130. Terron-Kwiatkowski A, Paller AS, Compton J, Atherton DJ, McLean WH, Irvine AD (2002) Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1. J Invest Dermatol 119:966–971

  131. Terron-Kwiatkowski A, Terrinoni A, Didona B, Melino G, Atherton DJ, Irvine AD, McLean WH (2004) Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene. Br J Dermatol 150:1096–1103

  132. Terron-Kwiatkowski A, van Steensel MA, van Geel M, Lane EB, McLean WH, Steijlen PM (2006) Mutation S233L in the 1B domain of keratin 1 causes epidermolytic palmoplantar keratoderma with “tonotubular” keratin. J Invest Dermatol 126:607–613

  133. Treiber M, Schulz HU, Landt O, Drenth JP, Castellani C, Real FX, Akar N, Ammann RW, Bargetzi M, Bhatia E, Demaine AG, Battagia C, Kingsnorth A, O’Reilly D, Truninger K, Koudova M, Spicak J, Cerny M, Menzel HJ, Moral P, Pignatti PF, Romanelli MG, Rickards O, De Stefano GF, Zarnescu NO, Choudhuri G, Sikora SS, Jansen JB, Weiss FU, Pietschmann M, Teich N, Gress TM, Ockenga J, Schmidt H, Kage A, Halangk J, Rosendahl J, Groneberg DA, Nickel R, Witt H (2006) Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer. J Mol Med 84:1015–1022

  134. Tsubota A, Akiyama M, Sakai K, Goto M, Nomura Y, Ando S, Abe M, Sawamura D, Shimizu H (2007) Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. J Invest Dermatol 127:1371–1374

  135. Tsubota A, Akiyama M, Kanitakis J, Sakai K, Nomura T, Claudy A, Shimizu H (2008a) Mild recessive bullous congenital ichthyosiform erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation. J Invest Dermatol 128:1648–1652

  136. Tsubota A, Akiyama M, Sakai K, Yanagi T, McMillan JR, Higashi A, Shimizu H (2008b) Congenital ichthyosiform erythroderma mimicking ichthyosis bullosa of Siemens. Br J Dermatol 158:191–194

  137. Uitto J, Pfendner E, Jackson LG (2003) Probing the fetal genome: progress in non-invasive prenatal diagnosis. Trends Mol Med 9:339–343

  138. Uitto J, Richard G, McGrath JA (2007) Diseases of epidermal keratins and their linker proteins. Exp Cell Res 313:1995–2009

  139. Uttam J, Hutton E, Coulombe PA, Anton-Lamprecht I, Yu QC, Gedde-Dahl T Jr, Fine JD, Fuchs E (1996) The genetic basis of epidermolysis bullosa simplex with mottled pigmentation. Proc Natl Acad Sci U S A 93:9079–9084

  140. van Steensel MA, Steijlen PM, Bladergroen RS, Vermeer M, van Geel M (2005) A missense mutation in the type II hair keratin hHb3 is associated with monilethrix. J Med Genet 42:e19

  141. Virtanen M, Smith SK, Gedde-Dahl T Jr, Vahlquist A, Bowden PE (2003) Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis. J Invest Dermatol 121:1013–1020

  142. Wang X, Shi Y, Ye Y, Liu F, Jin W, Chen W, Wang M, Hu L, Zhao G, Kong X (2001) Keratin 17 gene mutation in patients with steatocystoma multiplex. Zhonghua Yi Xue Za Zhi 81:540–543

  143. Werner NS, Windoffer R, Strnad P, Grund C, Leube RE, Magin TM (2004) Epidermolysis bullosa simplex-type mutations alter the dynamics of the keratin cytoskeleton and reveal a contribution of actin to the transport of keratin subunits. Mol Biol Cell 15:990–1002

  144. Wevers A, Kuhn A, Mahrle G (1991) Palmoplantar keratoderma with tonotubular keratin. J Am Acad Dermatol 24:638–642

  145. Whittock NV, Smith FJ, Wan H, Mallipeddi R, Griffiths WA, Dopping-Hepenstal P, Ashton GH, Eady RA, McLean WH, McGrath JA (2002) Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma. J Invest Dermatol 118:838–844

  146. Winter H, Rogers MA, Langbein L, Stevens HP, Leigh IM, Labreze C, Roul S, Taieb A, Krieg T, Schweizer J (1997) Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet 16:372–374

  147. Winter H, Schissel D, Parry DA, Smith TA, Liovic M, Birgitte Lane E, Edler L, Langbein L, Jave-Suarez LF, Rogers MA, Wilde J, Peters G, Schweizer J (2004) An unusual Ala12Thr polymorphism in the 1A alpha-helical segment of the companion layer-specific keratin K6hf: evidence for a risk factor in the etiology of the common hair disorder pseudofolliculitis barbae. J Invest Dermatol 122:652–657

  148. Xiao SX, Feng YG, Ren XR, Tan SS, Li L, Wang JM, Shi YZ (2004) A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset pachyonychia congenita type 2. J Invest Dermatol 122:892–895

  149. Yasukawa K, Sawamura D, McMillan JR, Nakamura H, Shimizu H (2002) Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. J Biol Chem 277:23670–23674

  150. Zlotogorski A, Marek D, Horev L, Abu A, Ben-Amitai D, Gerad L, Ingber A, Frydman M, Reznik-Wolf H, Vardy DA, Pras E (2006) An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J Invest Dermatol 126:1292–1296

Download references

Acknowledgments

This work was supported by network grants of the BMBF (Bundesministerium für Bildung und Forschung), Network for Ichthyoses and Related Keratinization disorders, NIRK (01GM0606) and Network Epidermolysis bullosa (01GM0614, 01GM0832) to MJA.

Author information

Correspondence to Meral Julia Arin.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Arin, M.J. The molecular basis of human keratin disorders. Hum Genet 125, 355–373 (2009). https://doi.org/10.1007/s00439-009-0646-5

Download citation

Keywords

  • Ectodermal Dysplasia
  • Tail Domain
  • Keratin Gene
  • Epidermolysis Bullosa Simplex
  • Hair Keratin