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Gene Review

KRT16  -  keratin 16, type I

Homo sapiens

Synonyms: CK-16, CK16, Cytokeratin-16, FNEPPK, K16, ...
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Disease relevance of KRT16

  • Keratins K6 and K16 are expressed in suprabasal interfollicular epidermis in wound healing and other pathological conditions associated with hyperproliferation, such as psoriasis and are induced when keratinocytes are cultured in vitro [1].
  • Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families [1].
  • The results demonstrate that both K16 and K17 expression are features of acute irritant contact dermatitis reactions, but suggest that the factors which influence and control their expression differ [2].
  • The replacement of these keratins in the suprabasal compartment by K6/K16 keratins that are made by all stratified squamous epithelia during hyperplasia rules out a truncated differentiation [3].
  • A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus [4].

High impact information on KRT16

  • Keratin 16 and keratin 17 mutations cause pachyonychia congenita [5].
  • We also show that Jadassohn-Lewandowsky PC is caused by a heterozygous missense mutation in the helix initiation peptide of K16 (Leu130Pro) [5].
  • Expression of keratin 16, as well as suprabasal integrin alpha 3 and insulin-like growth factor-1 receptors, was eliminated, whereas filagrin increased markedly [6].
  • Keratinocyte proteins that are expressed in abnormal sites of the epidermis during psoriasis, i.e., keratin 16, filaggrin, and involucrin, were, after PUVA treatment, localized to their normal sites [7].
  • Often the epidemic strain (type K16) was found not only in the patients' faeces but also on more remote skin sites such as hands, knees, groins, and the umbilicus [8].

Chemical compound and disease context of KRT16


Biological context of KRT16

  • Previous studies have shown linkage in these families to the type I keratin gene cluster at 17q12-q21 and this report shows that the cDNA of affected members of both families have novel heterozygous mutations in the expressed keratin 16 gene [1].
  • Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolytic palmoplantar keratoderma [12].
  • Recently, we have developed a long-range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene (KRT16A), without amplification of the two K16 pseudogenes (psiKRT16B and psiKRT16C), enabling mutation analysis based on genomic DNA [12].
  • The sequences of the two K16 genes showed striking homology not only within the coding sequences, but also within the intron positions and sequences and extending at least 400 base pairs 5' upstream and 850 base pairs 3' downstream from these genes [13].
  • We determined that two genes encoding K16 and three genes encoding K14 were clustered in two distinct segments of chromosome 17 [13].

Anatomical context of KRT16

  • Forced expression of human K16 in skin keratinocytes of transgenic mice causes a retraction of keratin filaments from the cell periphery, often in a polarized fashion [14].
  • In addition to their implications for the stable conformation of the keratin heterotetramers, these findings suggest that the tetramer-forming properties of K16 may influence its partitioning between the soluble and polymer pools, and hence contribute to its regulation in epithelial cells under resting and wound repair conditions [15].
  • Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton [16].
  • They therefore confirm that the PJE is a well-differentiated stratified epithelium with a complex unique phenotype that produces CKs specific for basal cells (CK 19), CKs associated with hyperproliferation (CK 16), and finally those associated with stratification (CKs 4 and 13) [17].
  • Keratins are the major structural proteins of the epidermis and associated appendages and the nail, hair follicle, palm, sole and tongue are the main sites of constitutive K6, K16 and K17 expression [18].

Associations of KRT16 with chemical compounds

  • A proline residue in the alpha-helical rod domain of type I keratin 16 destabilizes keratin heterotetramers [15].
  • One of these cDNA clones, HT27, isolated from the cDNA library of human tracheobronchial epithelial cells and whose expression in cultured cells was greatly suppressed by retinol, had a nucleotide sequence identical to the C-terminus of keratin 16 [19].
  • Multiple acetylated lysine residues have been identified in the N-terminal domain of H2B (K6, K11, K16, K17, K21, and K22), but little is known about how these modifications regulate transcription [20].
  • Specifically, while EGF induces expression of K6 and K16 keratin genes, retinoic acid suppresses their expression, and when both mediators are present simultaneously, the level of expression is intermediate, a product of both signals [21].
  • However, at the time of wound closure, when the epidermis is still hyperproliferative, alpha 2, alpha 3, alpha 6, and beta 1 were no longer confined to the basal layer, as in normal epidermis, but were also found in all the living suprabasal cell layers, coexpressed with the terminal differentiation markers involucrin, keratin 10, and keratin 16 [22].

Physical interactions of KRT16

  • The results obtained in this way demonstrated that PTHrP most probably binds to filaments built of cytokeratin 16 [23].

Regulatory relationships of KRT16

  • Ser63 and Ser73 on the c-Jun NH(2)-terminal transactivation domain could be phosphorylated in cells treated with EGF; nevertheless, we found that the c-Jun COOH terminus played a pivotal role in EGF-induced expression of keratin 16 [24].
  • K10-induced inhibition is reversed by the coexpression of K16 but not that of K14 [25].
  • CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not detected either in normal or in abnormal prostate tissues [26].
  • Taken together, the present data suggest that cholesteatoma is a hyperproliferative disease and that cholesteatoma expresses CK 16 near the external ear canal and transforms to express CK 13 during growth distally [27].

Other interactions of KRT16

  • The type I keratins 14 (K14) and 16 (K16) are distinct in their assembly properties and their expression pattern despite a high degree of sequence identity [15].
  • Strong induction of the wound-healing keratins K6, K16 and K17 was found in the suprabasal epidermis, which are not able to compensate for the lack of keratin 10 [28].
  • The parabasal cell layers reacted intensely to the cRNA probe complementary to CK16 mRNA, as were the reactions in the suprabasal cell layers of the PJE for the CK 13 and 4 probes [17].
  • At initial relapse, the symptomless skin adjacent to the relapsing lesion (margin) showed a marked expression of keratin 16 and EGFR [29].
  • This study is a report of a mosaic mutation in keratin 16 and also the association of a mutation in the V1 domain of a type I keratin associated with a human disease [4].

Analytical, diagnostic and therapeutic context of KRT16

  • Site-directed mutagenesis revealed that Pro188, an amino acid residue located in subdomain 1B of the rod, accounts quantitatively for the instability of K16-containing heterotetramers under denaturing conditions [15].
  • The mutation created a new BsmI restriction site and therefore, the mutation was confirmed in the patient and excluded from both parents and 50 normal, unrelated individuals by BsmI digestion of KRT16A polymerase chain reaction products [30].
  • Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments [12].
  • METHODS: Sixty-seven non-lesional and lesional skin samples from patients with psoriasis and normal skin from 19 non-psoriatic patients were studied by immunohistochemistry on frozen sections with K16 [31].
  • This, together with a similar strategy which we have developed for the K16 gene, provide a robust system for mutation detection and prenatal diagnosis for patients with PC-1 [32].


  1. Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. Shamsher, M.K., Navsaria, H.A., Stevens, H.P., Ratnavel, R.C., Purkis, P.E., Kelsell, D.P., McLean, W.H., Cook, L.J., Griffiths, W.A., Gschmeissner, S. Hum. Mol. Genet. (1995) [Pubmed]
  2. Keratin 17 is expressed during the course of SLS-induced irritant contact dermatitis, but unlike keratin 16, the degree of expression is unrelated to the density of dividing keratinocytes. Willis, C.M., Reiche, L., Wilkinson, J.D. Contact Derm. (1998) [Pubmed]
  3. Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing. Sun, T.T. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  4. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. Terrinoni, A., Puddu, P., Didona, B., De Laurenzi, V., Candi, E., Smith, F.J., McLean, W.H., Melino, G. J. Invest. Dermatol. (2000) [Pubmed]
  5. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. McLean, W.H., Rugg, E.L., Lunny, D.P., Morley, S.M., Lane, E.B., Swensson, O., Dopping-Hepenstal, P.J., Griffiths, W.A., Eady, R.A., Higgins, C. Nat. Genet. (1995) [Pubmed]
  6. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. Krueger, J.G., Wolfe, J.T., Nabeya, R.T., Vallat, V.P., Gilleaudeau, P., Heftler, N.S., Austin, L.M., Gottlieb, A.B. J. Exp. Med. (1995) [Pubmed]
  7. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. Vallat, V.P., Gilleaudeau, P., Battat, L., Wolfe, J., Nabeya, R., Heftler, N., Hodak, E., Gottlieb, A.B., Krueger, J.G. J. Exp. Med. (1994) [Pubmed]
  8. Gentamicin-resistant Klebsiella aerogenes in a urological ward. Casewell, M.W., Dalton, M.T., Webster, M., Phillips, I. Lancet (1977) [Pubmed]
  9. Normal human urothelial cells in vitro: proliferation and induction of stratification. Southgate, J., Hutton, K.A., Thomas, D.F., Trejdosiewicz, L.K. Lab. Invest. (1994) [Pubmed]
  10. Survival of multiply-resistant Klebsiella aerogenes and other gram-negative bacilli on finger-tips. Casewell, M.W., Desai, N. J. Hosp. Infect. (1983) [Pubmed]
  11. Outbreak of co-trimoxazole- and gentamicin-resistant Klebsiella aerogenes bacteremia in neutropenic patients receiving oral co-trimoxazole prophylaxis. Leahy, M.F., Humble, M.W. Australian and New Zealand journal of medicine. (1983) [Pubmed]
  12. Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1. Smith, F.J., Del Monaco, M., Steijlen, P.M., Munro, C.S., Morvay, M., Coleman, C.M., Rietveld, F.J., Uitto, J., McLean, W.H. Br. J. Dermatol. (1999) [Pubmed]
  13. A group of type I keratin genes on human chromosome 17: characterization and expression. Rosenberg, M., RayChaudhury, A., Shows, T.B., Le Beau, M.M., Fuchs, E. Mol. Cell. Biol. (1988) [Pubmed]
  14. Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16. Paladini, R.D., Takahashi, K., Bravo, N.S., Coulombe, P.A. J. Cell Biol. (1996) [Pubmed]
  15. A proline residue in the alpha-helical rod domain of type I keratin 16 destabilizes keratin heterotetramers. Wawersik, M., Paladini, R.D., Noensie, E., Coulombe, P.A. J. Biol. Chem. (1997) [Pubmed]
  16. Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Smith, F.J., Fisher, M.P., Healy, E., Rees, J.L., Bonifas, J.M., Epstein, E.H., Tan, E.M., Uitto, J., McLean, W.H. Exp. Dermatol. (2000) [Pubmed]
  17. In situ hybridization study of cytokeratin 4, 13, 16 and 19 mRNAs in human developing junctional epithelium. Feghali-Assaly, M., Sawaf, M.H., Ouhayoun, J.P. Eur. J. Oral Sci. (1997) [Pubmed]
  18. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Bowden, P.E., Haley, J.L., Kansky, A., Rothnagel, J.A., Jones, D.O., Turner, R.J. Nat. Genet. (1995) [Pubmed]
  19. Control of keratin gene expression by vitamin A in tracheobronchial epithelial cells. Huang, T.H., Ann, D.K., Zhang, Y.J., Chang, A.T., Crabb, J.W., Wu, R. Am. J. Respir. Cell Mol. Biol. (1994) [Pubmed]
  20. Deciphering the Roles of the Histone H2B N-Terminal Domain in Genome-Wide Transcription. Parra, M.A., Kerr, D., Fahy, D., Pouchnik, D.J., Wyrick, J.J. Mol. Cell. Biol. (2006) [Pubmed]
  21. Codominant regulation of keratin gene expression by cell surface receptors and nuclear receptors. Tomić-Canić, M., Freedberg, I.M., Blumenberg, M. Exp. Cell Res. (1996) [Pubmed]
  22. Aberrant integrin expression during epidermal wound healing and in psoriatic epidermis. Hertle, M.D., Kubler, M.D., Leigh, I.M., Watt, F.M. J. Clin. Invest. (1992) [Pubmed]
  23. PTHrP and cytokeratins in human epidermis. Seidel, J., Zabel, M., Kasprzak, A. Folia Histochem. Cytobiol. (2002) [Pubmed]
  24. Activation of extracellular signal-regulated kinase signaling by epidermal growth factor mediates c-Jun activation and p300 recruitment in keratin 16 gene expression. Wang, Y.N., Chen, Y.J., Chang, W.C. Mol. Pharmacol. (2006) [Pubmed]
  25. Modulation of cell proliferation by cytokeratins K10 and K16. Paramio, J.M., Casanova, M.L., Segrelles, C., Mittnacht, S., Lane, E.B., Jorcano, J.L. Mol. Cell. Biol. (1999) [Pubmed]
  26. Differential expression of cytokeratin mRNA and protein in normal prostate, prostatic intraepithelial neoplasia, and invasive carcinoma. Yang, Y., Hao, J., Liu, X., Dalkin, B., Nagle, R.B. Am. J. Pathol. (1997) [Pubmed]
  27. Expression of cytokeratins 13 and 16 in middle ear cholesteatoma. Sasaki, H., Huang, C.C. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. (1994) [Pubmed]
  28. A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. Müller, F.B., Huber, M., Kinaciyan, T., Hausser, I., Schaffrath, C., Krieg, T., Hohl, D., Korge, B.P., Arin, M.J. Hum. Mol. Genet. (2006) [Pubmed]
  29. The epidermal phenotype during initiation of the psoriatic lesion in the symptomless margin of relapsing psoriasis. Castelijns, F.A., Gerritsen, M.J., van Vlijmen-Willems, I.M., van Erp, P.E., van de Kerkhof, P.C. J. Am. Acad. Dermatol. (1999) [Pubmed]
  30. Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Connors, J.B., Rahil, A.K., Smith, F.J., McLean, W.H., Milstone, L.M. Br. J. Dermatol. (2001) [Pubmed]
  31. K16 expression in uninvolved psoriatic skin: a possible marker of pre-clinical psoriasis. Bhawan, J., Bansal, C., Whren, K., Schwertschlag, U. J. Cutan. Pathol. (2004) [Pubmed]
  32. A mutation detection strategy for the human keratin 6A gene and novel missense mutations in two cases of pachyonychia congenita type 1. Smith, F.J., McKenna, K.E., Irvine, A.D., Bingham, E.A., Coleman, C.M., Uitto, J., McLean, W.H. Exp. Dermatol. (1999) [Pubmed]
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