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). On review, mild nail changes were observed in some, but not all, of these patients. 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.
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 a kindred with autosomal dominant pachyonychia congenita 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 a 3-generation British Caucasian family, Covello et al. (1998) found the same N92S mutation in the KRT17 gene as the cause of Jackson-Lawler PC. The 18-year-old proband presented with rough skin due to follicular keratoses, and thickened nails and plantar skin. Although she did not have clinically obvious cysts, and had mild hyperkeratosis of the buccal mucosa, other family members had abnormal nails, blistering of the feet, and multiple cysts. Her mother had a history of painful keratoses and blistering on the feet, with thickened nails, yellowish cysts on the trunk and limbs, and recurrent flexural abscesses. She also had multiple milia. A lesion excised from the labium majus proved to be an epidermoid cyst. This family had previously been reported as having pachyonychia congenita with hidradenitis suppurativa (Todd et al., 1990). Covello et al. (1998) stated that within a single large pedigree (Munro et al., 1994), and indeed in a single individual with multiple cysts, they had found that some were true steatocysts and others keratinous cysts, some of which contained vellus hair. Scrotal and vulvar cystomatosis also form part of the syndrome.
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 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 steatocystoma multiplex, on restudy some but not all of the patients were found to have mild nail changes compatible with those of pachyonychia congenita. Affected individuals showed a severe phenotype consisting of myriads of cysts in the groin, perineum, axillae, trunk, and face. These were pictured by Smith et al. (1997). Histologic examination of cysts from the proband showed sebocytes within an epithelial wall characterized by slight epidermolytic hyperkeratosis. Nail changes were completely absent in the male proband who had myriads of cysts; however, his sister had slight thickening of the thumb nails and another sister had thickened fingernails but normal toenails. There was no family history of natal teeth but some members had mild focal nonepidermolytic palmoplantar keratoderma. Cysts in the steatocystoma families and the families with pachyonychia congenita of the Jackson-Lawler type (see 148069.0002 and 148069.0003), were indistinguishable clinically and histologically.
Terrinoni et al. (2001) reported this mutation in a patient with sporadic pachyonychia congenita (PC2; 167210).
Covello et al. (1998) described 2 unrelated kindreds with the identical missense arg94-to-cys (R94C) mutation in the 1A domain of keratin-17. However, whereas affected members of 1 kindred had the classic features of Jackson-Lawler pachyonychia congenita (PC2; 167210), affected persons in the other family had the steatocystoma multiplex phenotype (184500). The PC2 family consisted of affected mother and son; the affected steatocystoma multiplex family had affected mother, son, and daughter. The proband in the first family had a history of subcutaneous yellow nodules on the flexor surfaces of the arms, abdomen, and legs since puberty. She also had thickened nails of the feet. In the steatocystoma multiplex family, the 41-year-old Dutch Caucasian mother presented at an outpatient clinic because of what she described as 'acne present from puberty.' The number of lesions had increased with age; in addition to the face, lesions were present on the abdomen, arms, and legs. Her 4-year-old daughter and 11-year-old son were developing similar skin problems. Multiple nodules with varying diameter were found in the areas mentioned. None of the affected persons showed any nail changes or any 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 mother had developed thick dystrophic nails of the fingers and toes during childhood. In the second decade of life, she developed numerous cysts on the trunk as well as hidradenitis suppurativa in both axillae. The 5-year-old son was born with natal teeth and had cutaneous findings similar to those in the mother.
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 296T-C transition. This mutation may also be referred to as L15P.
In a patient with pachyonychia congenita (PC2; 167210), Hashiguchi et al. (2002) identified heterozygosity for a 452G-A (GTG to ATG) transition in the helix initiation motif of the KRT17 gene, resulting in a predicted val102-to-met (V102M) substitution.
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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]
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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]
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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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