Alternative titles; symbols
HGNC Approved Gene Symbol: KRT17
SNOMEDCT: 109433009; ICD10CM: L72.2;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:41,619,442-41,624,575 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Pachyonychia congenita 2 | 167210 | Autosomal dominant | 3 |
| Steatocystoma multiplex | 184500 | Autosomal dominant | 3 |
Among the members of the cytokeratin subfamily of intermediate filament (IF) proteins, cytokeratin-17 is remarkable since it is normally expressed in the basal cells of complex epithelia but not in stratified or simple epithelia. Troyanovsky et al. (1992) isolated a cDNA clone encoding KRT17 from a HeLa cDNA library. The KRT17 gene encodes a polypeptide of 432 amino acids with a calculated molecular mass of 48,000 Da. Synthesis of cytokeratin-17 seems to be a marker of basal cell differentiation in complex epithelia and therefore indicative of a certain type of epithelial 'stem cell.'
Troyanovsky et al. (1992) isolated a number of lambda-phage clones on chromosome 17 that covered 3 distinct, noncontiguous gene regions. Only one of these contained the functional KRT17 gene, which is located about 5 kb 5-prime upstream of the KRT16 gene (148067), whereas the other 2 contain unprocessed KRT17 pseudogenes. Each of these genes is part of the large keratin type I gene cluster on chromosome 17. The functional KRT17 gene differs from the pseudogenes by the extent of methylation of certain DNA sequences in the 5-prime upstream region. Using S1-nuclease protection assays and RNAs from several cell lines, Troyanovsky et al. (1992) identified a single transcriptional start point 26 nucleotides downstream from a TATA box element.
Troyanovsky et al. (1992) determined that the KRT17 gene is 5 kb long with 8 exons.
Kim et al. (2006) showed that keratin-17, an intermediate filament protein rapidly induced in wounded stratified epithelia, regulates cell growth through binding to the adaptor protein 14-3-3-sigma (601290). Mouse skin keratinocytes lacking keratin-17 show depressed protein translation and are of smaller size, correlating with decreased Akt/mTOR (164730/601231) signaling activity. Other signaling kinases have normal activity, pointing to the specificity of this defect. Two amino acid residues located in the N-terminal head domain of keratin-17 are required for the serum-dependent relocalization of 14-3-3-sigma from the nucleus to the cytoplasm, and for the concomitant stimulation of mTOR activity and cell growth. Kim et al. (2006) concluded that their findings revealed a new and unexpected role for the intermediate filament cytoskeleton in influencing cell growth and size by regulating protein synthesis.
In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside in the proximal nail matrix and are defined by high expression of keratin-14 (148066), keratin-17, and KI67 (MKI67; 176741). The mechanisms governing NSC differentiation are coupled directly to their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt (see 164820)-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, beta-catenin (116806) stabilization in the NSC region induced their regeneration. Takeo et al. (2013) concluded that their results established a link between nail stem cell differentiation and digit regeneration, and suggested that NSCs may have the potential to contribute to the development of novel treatments for amputees.
McLean et al. (1995) found a mutation in the KRT17 gene (148069.0001) in a large Scottish kindred in which pachyonychia congenita had been shown to be linked to markers that mapped within the type I keratin cluster on 17q (PC2; 167210) (Munro et al., 1994).
Smith et al. (1997) reported heterozygous KRT17 missense mutations in the same conserved protein motif in a further 5 families with PC, described as having the Jackson-Lawler type. They also showed heterozygous missense mutations in KRT17 in 2 families diagnosed with steatocystoma multiplex (see 148069.0004 and 148069.0005). On review, mild nail changes were observed in some, but not all, of these patients. Cysts in the steatocystoma families and the families with pachyonychia congenita of the Jackson-Lawler type were indistinguishable clinically and histologically. They concluded that phenotypic variation is observed with KRT17 mutations as is the case with other keratin disorders.
KRT17 is expressed in the nail bed, hair follicle, sebaceous glands, and other epidermal appendages. Covello et al. (1998) described 3 unrelated kindreds carrying KRT17 mutations. Two of these families had identical missense mutations (R94C; 148069.0006) in the 1A domain of KRT17. However, whereas affected members of 1 kindred had the classic features of Jackson-Lawler pachyonychia congenita, affected persons in the other family had the steatocystoma multiplex phenotype. In a third family with pachyonychia congenita, an N92S mutation (148069.0002) was detected.
In a mother and son of Caribbean origin with Jackson-Lawler pachyonychia congenita, Celebi et al. (1999) identified heterozygosity for a missense mutation in KRT17 (M88T; 148069.0007).
In 3 unrelated probands with PC2, Smith et al. (2001) identified heterozygosity for mutations in exon 1 of the KRT17 gene, including a 15-bp deletion in the proband from an Italian Caucasian family (148069.0008), which the authors noted was the first report of a deletion in KRT17. The other 2 probands had missense mutations, an R94P substitution in an Australian Caucasian female (148069.0009), and an L95Q substitution in a French Caucasian female (148069.0010). The authors observed that the deletion produced a similar clinical phenotype to that seen with missense mutations in KRT17.
In a cohort of 13 probands with clinically heterogeneous pachyonychia congenita, Terrinoni et al. (2001) screened for mutations in the K6A (148041), K16 (148067), and K17 genes, and identified 4 patients with heterozygous missense mutations in the K17 gene. Three of the patients carried novel mutations (148069.0011-148069.0013), and 1 patient had a mutation that had previously been reported in a family with steatocystoma multiplex (R94H; 148069.0005).
In a 19-year-old Japanese man with PC, Hashiguchi et al. (2002) directly sequenced the KRT17 gene and identified identified heterozygosity for a de novo missense mutation (V102M; 148069.0014). The variant was not found in his unaffected parents or in 50 Japanese controls.
In an affected father, daughter, and granddaughter from a large 5-generation Asian family with PC, Kanda et al. (2009) sequenced the KRT6B (148042) and KRT17 genes and identified heterozygosity for the previously reported L99P mutation in the KRT17 gene (148069.0013). The mutation was not found in 50 control individuals.
K17-null mice develop alopecia in the first week after birth, correlating with hair shaft fragility and untimely apoptosis in the hair bulb (McGowan et al., 2002). Tong and Coulombe (2006) showed that this abnormal apoptosis reflected premature entry into catagen. K17-null skin keratinocytes in primary culture were more sensitive to Tnf (191160) than to other proapoptotic challenges. K17 interacted with Tradd (603500), a death adaptor essential for Tnf receptor-1 (TNFRSF1A; 191190)-dependent signal transduction, suggesting a functional link between K17 and TNF signaling. The activity of Nfkb (see 164011), a downstream target of Tnf, was increased in K17-null skin. Ablation of Tnf partly rescued the hair cycling defect of K17-null mice.
Gli2(tg) mice are transgenic mice that overexpress the hedgehog signaling protein Gli2 (165230) and develop basal cell carcinoma (BCC; see 605462) and basaloid follicular hamartoma. DePianto et al. (2010) found that expression of Krt17 was induced before the onset of lesions in the epidermis of Gli2(tg) mice. Deletion of Krt17 in Gli2(tg) mice reduced the inflammatory response and the frequency of mitotically active cells, and it resulted in better preservation of skin barrier function. Absence of Krt17 in Gli2(tg) Krt17 -/- skin correlated with reduction in T-helper-1 (Th1) proinflammatory and Th17 antimicrobial T cells and induction of Th2 antiinflammatory markers. Deletion of Krt17 also downregulated BCC-related matrix metalloproteases (e.g., MMP3; 185250) and normalized altered cytokine expression. Phorbol ester treatment enhanced proliferation of Gli2(tg) cells, but not Gli2(tg) Krt17 -/- cells. DePianto et al. (2010) concluded that KRT17 has a role in modulating the immune response in hedgehog-driven basaloid skin tumors.
In affected members of the large 5-generation Scottish kindred with autosomal dominant pachyonychia congenita, mapped to chromosome 17q12-q21 by Munro et al. (1994) and described as the Jackson-Lawler type (PC2; 167210), McLean et al. (1995) found heterozygosity for an asn92-to-asp (N92D) missense mutation in the helix initiation motif of keratin-17.
In a family in which 5 individuals in 3 generations had pachyonychia congenita described as the Jackson-Lawler type (PC2; 167210), Smith et al. (1997) found an A-to-G transition in the KRT17 gene, producing a predicted asn92-to-ser (N92S) substitution. The identical mutation was found in 3 sporadic cases. The mutation created a new DdelI site.
In affected members of a 3-generation British Caucasian family with PC2, originally described by Todd et al. (1990) as having pachyonychia with hidradenitis suppurativa, Covello et al. (1998) identified heterozygosity for the N92S mutation in the KRT17 gene.
In a family in which the father and 2 daughters had pachyonychia congenita described as the Jackson-Lawler type (PC2; 167210), Smith et al. (1997) identified a heterozygous 440T-G transversion in the KRT17 gene, producing a tyr98-to-asp (Y98D) substitution in affected individuals.
In a mother and daughter with steatocystoma multiplex (184500), Smith et al. (1997) demonstrated heterozygosity for the transversion 422A-C in the KRT17 gene, which was predicted to produce an asn92-to-his (N92H) substitution.
In a kindred in which 8 individuals in 3 generations had steatocystoma multiplex (184500), Smith et al. (1997) found heterozygosity for a purine transition, c.429G-A, causing a predicted arg94-to-his (R94H) substitution. The mutation occurred in residue 10 of the KRT17 helix initiation peptide and potentially was a CpG deamination mutation. Although originally diagnosed with steatocystoma multiplex, on restudy some but not all of the patients were found to have mild nail changes compatible with those of pachyonychia congenita (see PC2, 167210).
Terrinoni et al. (2001) reported this mutation in a patient with sporadic pachyonychia congenita (PC2).
Covello et al. (1998) reported 2 unrelated kindreds with the identical missense mutation (arg94-to-cys; R94C) in the 1A domain of keratin-17. However, whereas the affected mother and son of the first kindred had the classic features of Jackson-Lawler pachyonychia congenita (PC2; 167210), the affected Dutch Caucasian mother, son, and daughter in the second family had the steatocystoma multiplex phenotype (184500) without any nail changes or other skin, hair, or mucosal abnormalities.
Celebi et al. (1999) described a mother and son of Caribbean origin with Jackson-Lawler pachyonychia congenita (PC; 167210) due to heterozygosity for a met88-to-thr mutation (M88T) resulting from an ATG-to-ACG change in the KRT17 gene. The mutation was not found in the proband's unaffected mother or in 50 unrelated controls; DNA was unavailable from her father.
In an Italian Caucasian family with Jackson-Lawler pachyonychia congenita (PC2; 167210) described by Clementi et al. (1986), Smith et al. (2001) reported a novel heterozygous 15-bp deletion in the KRT17 gene, 279del15. This was the first report of a deletion in KRT17 and led to removal of the amino acid sequence RLASY (R94-98del) from the highly conserved 1A domain of the KRT17 protein (deletion of 1A domain residues 10-14).
In an Australian Caucasian female with sporadic Jackson-Lawler pachyonychia congenita (PC2; 167210), Smith et al. (2001) reported a novel heterozygous arg94-to-pro (R94P) mutation that arose from a 281G-C transversion in the KRT17 gene. This mutation occurred within the helix initiation 1A domain hotspot for pathogenic keratin mutations.
In a French Caucasian female with sporadic Jackson-Lawler pachyonychia congenita (PC2; 167210), Smith et al. (2001) reported a novel heterozygous 284T-A transversion in the KRT17 gene, resulting in a leu95-to-gln (L95Q) amino acid substitution. This mutation occurred within the helix initiation 1A domain hotspot for pathogenic keratin mutations.
In a patient with sporadic pachyonychia congenita (PC2; 167210), Terrinoni et al. (2001) reported a leu95-to-pro (L95P) mutation in the 1A domain of the KRT17 protein, resulting from a 284T-C transition. This mutation may also be referred to as L11P.
In a patient with sporadic pachyonychia congenita (PC2; 167210), Terrinoni et al. (2001) reported a deletion of 3 nucleotides at position 289 of the KRT17 gene (289delCCT), predicting deletion of serine-97 (S97del) in the 1A domain. This mutation may also be referred to as S13del.
In a family with pachyonychia congenita (PC2; 167210), Terrinoni et al. (2001) identified a leu99-to-pro (L99P) mutation in the 1A domain of the KRT17 protein, resulting from a c.296T-C transition. This mutation may also be referred to as L15P.
In an affected father, daughter, and granddaughter from a large 5-generation Asian family with pachyonychia congenita, Kanda et al. (2009) sequenced the KRT6B (148042) and KRT17 genes and identified heterozygosity for the previously reported L99P mutation in the KRT17 gene (148069.0013). The mutation was not found in 50 control individuals. Genetic analysis of cystic tissue from the proband and her father showed the L99P mutation in 1 allele, as seen in the family's peripheral blood. There was no evidence for loss of heterozygosity or second-hit mutations, and the authors concluded that the cysts in PC2 are benign, and their formation does not require a complete functional loss of keratin.
In a 19-year-old Japanese man with pachyonychia congenita (PC2; 167210), Hashiguchi et al. (2002) identified heterozygosity for a de novo 452G-A (GTG to ATG) transition in the KRT17 gene, resulting in a val102-to-met (V102M) substitution within the highly conserved helix initiation motif 1A domain. The mutation was not found in 50 Japanese controls.
Celebi, J. T., Tanzi, E. L., Yao, Y. J., Michael, E. J., Peacocke, M. Identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. J. Invest. Derm. 113: 848-850, 1999. [PubMed: 10571744] [Full Text: https://doi.org/10.1046/j.1523-1747.1999.00762.x]
Clementi, M., Cardin de Stefani, E., Dei Rossi, C., Avventi, V., Tenconi, R. Pachyonychia congenita Jackson-Lawler type: a distinct malformation syndrome. Brit. J. Derm. 114: 367-370, 1986. [PubMed: 3954955] [Full Text: https://doi.org/10.1111/j.1365-2133.1986.tb02829.x]
Covello, S. P., Smith, F. J. D., Sillevis Smitt, J. H., Paller, A. S., Munro, C. S., Jonkman, M. F., Uitto, J., McLean, W. H. I. Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Brit. J. Derm. 139: 475-480, 1998. [PubMed: 9767294] [Full Text: https://doi.org/10.1046/j.1365-2133.1998.02413.x]
DePianto, D., Kerns, M. L., Dlugosz, A. A., Coulombe, P. A. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nature Genet. 42: 910-914, 2010. [PubMed: 20871598] [Full Text: https://doi.org/10.1038/ng.665]
Hashiguchi, T., Yotsumoto, S., Shimada, H., Terasaki, K., Setoyama, M., Kobayashi, K., Saheki, T., Kanzaki, T. A novel point mutation in the keratin 17 gene in a Japanese case of pachyonychia congenita type 2. (Letter) J. Invest. Derm. 118: 545-547, 2002. [PubMed: 11874497] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01701.x]
Kanda, M., Natsuga, K., Nishie, W., Akiyama, M., Nagasaki, A., Shimizu, T., Shimizu, H. Morphological and genetic analysis of steatocystoma multiplex in an Asian family with pachyonychia congenita type 2 harbouring a KRT17 missense mutation. Brit. J. Derm. 160: 465-468, 2009. [PubMed: 19120334] [Full Text: https://doi.org/10.1111/j.1365-2133.2008.08983.x]
Kim, S., Wong, P., Coulombe, P. A. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441: 362-365, 2006. [PubMed: 16710422] [Full Text: https://doi.org/10.1038/nature04659]
McGowan, K. M., Tong, X., Colucci-Guyon, E., Langa, F., Babinet, C., Coulombe, P. A. Keratin 17 null mice exhibit age- and strain-dependent alopecia. Genes Dev. 16: 1412-1422, 2002. [PubMed: 12050118] [Full Text: https://doi.org/10.1101/gad.979502]
McLean, W. H. I., Rugg, E. L., Lunny, D. P., Morley, S. M., Lane, E. B., Swensson, O., Dopping-Hepenstal, P. J. C., Griffiths, W. A. D., Eady, R. A. J., Higgins, C., Navsaria, H. A., Leigh, I. M., Strachan, T., Kunkeler, L., Munro, C. S. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nature Genet. 9: 273-278, 1995. [PubMed: 7539673] [Full Text: https://doi.org/10.1038/ng0395-273]
Munro, C. S., Carter, S., Bryce, S., Hall, M., Rees, J. L., Kunkeler, L., Stephenson, A., Strachan, T. A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21. J. Med. Genet. 31: 675-678, 1994. [PubMed: 7529318] [Full Text: https://doi.org/10.1136/jmg.31.9.675]
Smith, F. J. D., Coleman, C. M., Bayoumy, N. M., Tenconi, R., Nelson, J., David, A., McLean, W. H. I. Novel keratin 17 mutations in pachyonychia congenita type 2. J. Invest. Derm. 116: 806-808, 2001. [PubMed: 11348474] [Full Text: https://doi.org/10.1046/j.1523-1747.2001.01335.x]
Smith, F. J. D., Corden, L. D., Rugg, E. L., Ratnavel, R., Leigh, I. M., Moss, C., Tidman, M. J., Hohl, D., Huber, M., Kunkeler, L., Munro, C. S., Lane, E. B., McLean, W. H. I. Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J. Invest. Derm. 108: 220-223, 1997. [PubMed: 9008238] [Full Text: https://doi.org/10.1111/1523-1747.ep12335315]
Takeo, M., Chou, W. C., Sun, Q., Lee, W., Rabbani, P., Loomis, C., Taketo, M. M., Ito, M. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499: 228-232, 2013. [PubMed: 23760480] [Full Text: https://doi.org/10.1038/nature12214]
Terrinoni, A., Smith, F. J. D., Didona, B., Canzona, F., Paradisi, M., Huber, M., Hohl, D., David, A., Verloes, A., Leigh, I. M., Munro, C. S., Melino, G., McLean, W. H. I. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J. Invest. Derm. 117: 1391-1396, 2001. [PubMed: 11886499] [Full Text: https://doi.org/10.1046/j.0022-202x.2001.01565.x]
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Tong, X., Coulombe, P. A. Keratin 17 modulates hair follicle cycling in a TNF-alpha-dependent fashion. Genes Dev. 20: 1353-1364, 2006. [PubMed: 16702408] [Full Text: https://doi.org/10.1101/gad.1387406]
Troyanovsky, S. M., Leube, R. E., Franke, W. W. Characterization of the human gene encoding cytokeratin 17 and its expression pattern. Europ. J. Cell Biol. 59: 127-137, 1992. [PubMed: 1281771]