Alternative titles; symbols
HGNC Approved Gene Symbol: KRT8
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,897,191-52,949,860 (from NCBI)
Keratin 8 is a type II keratin (Moll et al., 1982). Endo A is the mouse equivalent. Endo B, which is the equivalent of human keratin 18 (148070), a type I keratin, is coexpressed with Endo A; the 2 appear to be the first intermediate filament (IF) proteins expressed during murine development (Jackson et al., 1980). Yamamoto et al. (1990) studied a full-length cDNA for cytokeratin 8 from placenta. They determined the distribution of cytokeratin 8 mRNA in various fetal tissues and in placentae of different gestational ages.
Krauss and Franke (1990) cloned cytokeratin 8 from a genomic library. The 485-amino acid protein deduced from the exon sequences has a calculated molecular mass of about 53.5 kD. CK8 shows strong homology with the corresponding bovine, mouse, and Xenopus proteins. The human and mouse CK8 share about 82% identity in the N-terminal head domain, 95% identity in the alpha helical rod domain, and 67.5% identity in the C-terminal tail.
He et al. (2002) presented evidence that soluble depolymerized K8 subunits were phosphorylated on ser73 by c-Jun N-terminal kinase (JNK1; 601158) upon stimulation of the proapoptotic cytokine receptor Fas (134637) in colon carcinoma cells. K8 was also phosphorylated following exposure to ultraviolet light. Coimmunoprecipitation studies indicated that JNK interacted directly with K8, and K8 was able to sequester a substantial amount of the 54-kD isoform of JNK. The association of JNK with K8 correlated with the decreased ability of JNK to phosphorylate endogenous c-Jun (see 165160). He et al. (2002) hypothesized that K8 phosphorylation could regulate JNK signaling and/or keratin dynamics. Ku et al. (2002) reported the phosphorylation of K8 ser73 by p38 mitogen-activated protein kinase (MAPK14; 600289). p38 MAPK associated with K8/K18 complexes in transfected baby hamster kidney cells, phosphorylated K8 on ser73, and bound specifically to K8 in vitro. Ku et al. (2002) noted that the leu160-to-pro mutation in K1 (139350.0002) leads to epidermolytic hyperkeratosis (113800). The comparable mutation in K8 resulted in hyperphosphorylation of K8 due to neophosphorylation of ser70 in addition to phosphorylation of ser73, and keratin filament collapse in the presence of okadaic acid, a phosphatase inhibitor.
Krauss and Franke (1990) determined that the CK8 gene contains 8 exons instead of 9 as is found in all other type II cytokeratins due to lack of intron 5, and the gene spans over 8.8 kb. The 5-prime flanking region contains a TATA box, 1 SP1 (189906) motif, and an Alu-like sequence in an orientation opposite that of the CK8 gene. Intron 1 is long (about 2.5 kb) and contains 3 SP1 sites, 1 AP1 (see 165160) site, and another Alu element in the same orientation as CK8.
Keratins 8 and 18 of simple epithelia differ from the keratins of stratified epithelia in tissue expression and regulation. Using PCR to study DNAs from somatic cell hybrids, Waseem et al. (1990) located a single active gene for keratin 8 on chromosome 12. This chromosome contains several genes for type II keratins and also the gene for keratin 18, the type I keratin that is coexpressed with keratin 8. This location of both members of a keratin pair on a single chromosome is unique among keratin genes; it is consistent with the hypothesis that keratins 8 and 18 may be closer to an ancestral gene than the keratins of more highly differentiated epithelia.
About 10% of patients who undergo liver transplantation have cryptogenic liver disease. In animal models, the absence of heteropolymeric keratins 8 and 18 or the presence of mutant keratins in hepatocytes causes or promotes liver disease. Ku et al. (1997) demonstrated a germline mutation in keratin 18 (148070.0001) in 1 of 28 patients with cryptogenic cirrhosis (see 215600). Of 55 patients with cryptogenic liver disease screened by Ku et al. (2001), 5 unrelated patients had mutations in the keratin 8 gene that appeared to have predisposed them to the disease. Three patients had a gly61-to-cys mutation at a highly conserved glycine (148060.0001), and the other 2 had a tyr53-to-his mutation (148060.0002). These mutations were not detected in patients with other forms of liver disease or in randomly selected patients. In transfected cells, the gly61-to-cys mutation limited keratin filament reorganization when the cells were exposed to oxidative stress. In contrast, the tyr53-to-his mutation destabilized keratin filaments when transfected cells were exposed to heat or okadaic acid stress.
Following up on the observation that KRT8 and KRT18 mutations are found in patients with cryptogenic cirrhosis, Ku et al. (2003) investigated the role of keratin mutations in noncryptogenic cirrhosis and the incidence of keratin mutations in the general population. The results suggested that K8 and K18 are likely susceptibility genes for developing both cryptogenic and noncryptogenic forms of liver disease. They studied 314 liver explants of patients who primarily had noncryptogenic cirrhosis and compared the results with 349 blood bank volunteers. Seven unique K8/K18 mutations were found in 11 independent patients with biliary atresia, hepatitis B/C, alcoholism, primary biliary cirrhosis, and fulminant hepatitis. Seven of the 11 patients had mutations previously described in patients with cryptogenic cirrhosis: gly61 to cys (G61C; 148060.0001), tyr53 to his (Y53H; 148060.0002), and his127 to leu (H127L; 148070.0001). Of the 349 blood bank control samples, only 1 contained the tyr53-to-his mutation and 1 the gly61-to-cys mutation. Livers with keratin mutations had cytoplasmic filamentous deposits that were less frequent in livers without the mutations (P = 0.03).
Halangk et al. (2004) studied the frequency of the G61C and Y53H mutations in the KRT8 gene in 1,667 patients with various liver diseases, including cirrhosis, and in 679 healthy controls. The G62C variant was found in 27 patients (1.6%) in 12 controls (1.8%). The Y53H variant was found in 2 patients (0.1%) and in 1 control (0.1%). Halangk et al. (2004) concluded that mutations in the KRT8 gene do not predispose to chronic liver disease, including cryptogenic cirrhosis.
Casanova et al. (1999) generated mice expressing the human KRT8 gene, leading to a moderate increase in the content of keratin in simple epithelia. These mice displayed progressive exocrine pancreas alterations, including dysplasia and loss of acinar architecture, redifferentiation of acinar to ductal cells, inflammation, fibrosis, and substitution of exocrine by adipose tissue, as well as increased cell proliferation and apoptosis. The phenotype was very similar to that reported for transgenic mice expressing a dominant-negative mutant TGF-beta type II receptor (TGFBR2; 190182). Casanova et al. (1999) showed that these Tgfbr2 mutant mice also had elevated KRT8/KRT18 levels. The results indicated that simple epithelial keratins play a relevant role in the regulation of exocrine pancreas homeostasis and supported the idea that disruption of mechanisms that normally regulate keratin expression in vivo could be related to inflammatory and neoplastic pancreatic disorders.
Jaquemar et al. (2003) determined that the lethality seen in genetically sensitive K8-null mouse embryos is due to disruption of the trophoblast giant cell layer that normally forms a barrier between the maternal and embryonic compartments. Massive hemorrhages of maternal blood were found between the decidua capsularis and the parietal yolk sac. Maternal tumor necrosis factor (TNF; 191160) and TNF receptor (see 191190) contributed to the lethality.
This variant, formerly titled CIRRHOSIS, CRYPTOGENIC OR NONCRYPTOGENIC, SUSCEPTIBILITY TO, has been reclassified as a variant of unknown significance based on the findings of Halangk et al. (2004).
In 3 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al. (2001) found a gly61-to-cys (G61C) missense mutation in the keratin 8 gene.
Ku et al. (2003) found the G61C mutation in a few patients with noncryptogenic cirrhosis, and concluded that this mutation causes susceptibility to noncryptogenic cirrhosis.
Halangk et al. (2004) studied the frequency of the G61C variant in the KRT8 gene in 1,667 patients with various liver diseases, including cirrhosis, and in 679 healthy controls. The G62C variant was found in 27 patients (1.6%) in 12 controls (1.8%). Halangk et al. (2004) concluded that the G61C variant does not predispose to chronic liver disease, including cryptogenic cirrhosis.
This variant, formerly titled CIRRHOSIS, CRYPTOGENIC, has been reclassified as a variant of unknown significance based on the findings of Halangk et al. (2004).
In 2 of 55 patients with cryptogenic cirrhosis (see 215600), Ku et al. (2001) found a tyr53-to-his (T53H) missense mutation in the KRT8 gene.
Halangk et al. (2004) studied the frequency of the Y53H variant in the KRT8 gene in 1,667 patients with various liver diseases, including cirrhosis, and in 679 healthy controls. The Y53H variant was found in 2 patients (0.1%) and in 1 control (0.1%). Halangk et al. (2004) concluded that the Y53H variant gene does not predispose to chronic liver disease, including cryptogenic cirrhosis.
Casanova, M. L., Bravo, A., Ramirez, A., Morreale de Escobar, G., Were, F., Merlino, G., Vidal, M., Jorcano, J. L. Exocrine pancreatic disorders in transsgenic (sic) mice expressing human keratin 8. J. Clin. Invest. 103: 1587-1595, 1999. [PubMed: 10359568] [Full Text: https://doi.org/10.1172/JCI5343]
Halangk, J., Berg, T., Puhl, G., Mueller, T., Nickel, R., Kage, A., Landt, O., Luck, W., Wiedenmann, B., Neuhaus, P., Witt, H. Keratin 8 Y54H and G62C mutations are not associated with liver disease. J. Med. Genet. 41: e92, 2004. [PubMed: 15235035] [Full Text: https://doi.org/10.1136/jmg.2003.011650]
He, T., Stepulak, A., Holmstrom, T. H., Omary, M. B., Eriksson, J. E. The intermediate filament protein kinase 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase. J. Biol. Chem. 277: 10767-10774, 2002. [PubMed: 11781324] [Full Text: https://doi.org/10.1074/jbc.M111436200]
Jackson, B. W., Grund, C., Schmid, E., Burke, K., Franke, W., Illmensee, K. Formation of cytoskeletal elements during mouse embryogenesis: intermediate filaments of the cytokeratin type and desmosomes in preimplantation embryos. Differentiation 17: 161-179, 1980. [PubMed: 6161051] [Full Text: https://doi.org/10.1111/j.1432-0436.1980.tb01093.x]
Jaquemar, D., Kupriyanov, S., Wankell, M., Avis, J., Benirschke, K., Baribault, H., Oshima, R. G. Keratin 8 protection of placental barrier function. J. Cell Biol. 161: 749-756, 2003. [PubMed: 12771125] [Full Text: https://doi.org/10.1083/jcb.200210004]
Krauss, S., Franke, W. W. Organization and sequence of the human gene encoding cytokeratin 8. Gene 86: 241-249, 1990. [PubMed: 1691124] [Full Text: https://doi.org/10.1016/0378-1119(90)90285-y]
Ku, N.-O., Azhar, S., Omary, M. B. Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease-causing mutation. J. Biol. Chem. 277: 10775-10782, 2002. [PubMed: 11788583] [Full Text: https://doi.org/10.1074/jbc.M107623200]
Ku, N.-O., Darling, J. M., Krams, S. M., Esquivel, C. O., Keeffe, E. B., Sibley, R. K., Lee, Y. M., Wright, T. L., Omary, M. B. Keratin 8 and 18 mutations are risk factors for developing liver disease of multiple etiologies. Proc. Nat. Acad. Sci. 100: 6063-6068, 2003. [PubMed: 12724528] [Full Text: https://doi.org/10.1073/pnas.0936165100]
Ku, N.-O., Gish, R., Wright, T. L., Omary, M. B. Keratin 8 mutations in patients with cryptogenic liver disease. New Eng. J. Med. 344: 1580-1587, 2001. [PubMed: 11372009] [Full Text: https://doi.org/10.1056/NEJM200105243442103]
Ku, N.-O., Wright, T. L., Terrault, N. A., Gish, R., Omary, M. B. Mutation of human keratin 18 in association with cryptogenic cirrhosis. J. Clin. Invest. 99: 19-23, 1997. [PubMed: 9011570] [Full Text: https://doi.org/10.1172/JCI119127]
Moll, R., Franke, W. W., Schiller, D. L., Geiger, B., Krepler, R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31: 11-24, 1982. [PubMed: 6186379] [Full Text: https://doi.org/10.1016/0092-8674(82)90400-7]
Waseem, A., Alexander, C. M., Steel, J. B., Lane, E. B. Embryonic simple epithelial keratins 8 and 18: chromosomal location emphasizes difference from other keratin pairs. New Biologist 2: 464-478, 1990. [PubMed: 1705144]
Yamamoto, R., Kao, L.-C., McKnight, C. E., Strauss, J. F., III. Cloning and sequence of cDNA for human placental cytokeratin 8: regulation of the mRNA in trophoblastic cells by cAMP. Molec. Endocr. 4: 370-374, 1990. [PubMed: 1692965] [Full Text: https://doi.org/10.1210/mend-4-3-370]