Alternative titles; symbols
HGNC Approved Gene Symbol: KRT6C
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38) : 12:52,468,516-52,473,805 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Palmoplantar keratoderma, nonepidermolytic, focal or diffuse | 615735 | Autosomal dominant | 3 |
KRT6C belongs to the keratin family of epithelial-specific intermediate filament proteins. Keratins expressed in 'soft' epithelial tissues (i.e., excluding hair and nail) have been subdivided into type I and type II keratins. As keratin filament assembly begins with the formation of a type I-type II heterodimer, epithelial cells express at least 1 member of each subtype. Pairwise keratin gene expression is regulated in an epithelial tissue-type and differentiation-specific manner, creating patterns that are highly conserved among mammalian species (summary by Takahashi et al., 1995).
By screening a skin cDNA library with probes derived from the KRT6A gene (148041), Takahashi et al. (1995) cloned KRT6C, which they designated K6E. Like the other K6 proteins, the deduced K6E protein contains 564 amino acids, and it has a calculated molecular mass of 60.2 kD. K6E shares at least 97.6% identity with other K6 proteins.
By RT-PCR, Wilson et al. (2010) demonstrated that KRT6C is expressed in mRNA derived from the plantar epidermis.
Hartz (2008) mapped the KRT6C gene to chromosome 12q13.13 based on an alignment of the KRT6C sequence (GenBank L42611) with the genomic sequence (build 36.1).
In 3 families with focal palmoplantar keratoderma (615735), in which affected individuals were negative for mutation in the KRT6A and KRT6B (148042) genes, Wilson et al. (2010) identified heterozygosity for in-frame deletions in KRT6C (612315.0001 and 612315.0002). The affected individuals had very minor or absent nail changes and relatively mild, site-restricted keratoderma.
In 3 affected members of a Japanese family with focal or diffuse keratoderma in a primarily plantar distribution, who were negative for mutation in the KRT6A, KRT6B, KRT16 (148067), and KRT17 (148069) genes, Akasaka et al. (2011) identified a heterozygous missense mutation in the KRT6C gene (E472K; 612315.0003).
In a father and daughter with focal plantar keratoderma, Kubo et al. (2013) sequenced the candidate gene KRT6C and identified heterozygosity for the E472K mutation, which was not present in an unaffected son. Transfection studies in HaCaT cells showed collapse of the keratin filament network in a dose-dependent manner, suggesting that the mutation has a dominant-negative effect on keratin filament network formation.
In a father and son in 1 family as well as the affected members of an unrelated 4-generation family with focal palmoplantar keratoderma (PPKNEFD; 615735), Wilson et al. (2010) identified heterozygosity for a 3-bp deletion (c.516_518delCAA) in exon 1 of the KRT6C gene, resulting in an in-frame deletion (Asn172del) within the conserved N-terminal end of the helix 1A domain. The mutation segregated with disease in both families; however, the 3-bp deletion was also present in 3 of 335 population controls. Wilson et al. (2010) suggested that this KRT6C mutation might exist at a low level in the general population, but that the relatively mild plantar callus formation associated with the mutation might not always come to clinical attention.
In affected members of a 4-generation family with focal palmoplantar keratoderma (PPKNEFD; 615735), Wilson et al. (2010) identified heterozygosity for a 27-bp deletion (c.1384_1410del27) in exon 7 of the KRT6C gene. This mutation resulted in an in-frame deletion (Ile462_Glu470del) with loss of most of the highly conserved helix termination motif from the helix 2B domain, a sequence critically important for keratin intermediate filament assembly. The mutation was not found in unaffected family members or in 354 population controls.
In 3 affected members of a Japanese family with focal or diffuse palmoplantar keratoderma (PPKNEFD; 615735), Wilson et al. (2010) identified heterozygosity for a c.1414G-A transition in exon 7 of the KRT6C gene, resulting in a glu472-to-lys (E472K) substitution at a conserved residue in the C terminus of the 2B domain. The mutation, which segregated with disease in the family, was not found in 104 controls.
In a father and daughter with focal plantar keratoderma, Kubo et al. (2013) sequenced the candidate gene KRT6C and identified heterozygosity for the E472K mutation, which was not present in an unaffected son. Palmar skin as well as the nails of hands and feet were normal in the affected individuals. Analysis of transfected HaCaT cells showed that cells expressing low levels of mutant protein exhibited no alterations in the keratin filament network, whereas cells expressing high levels displayed a collapsed network of keratin filaments. Semiquantification of exogenously expressed KRT6C confirmed that the collapse of the keratin filament network occurred in a manner dependent on the level of expression of mutant keratin-6c.
Akasaka, E., Nakano, H., Nakano, A., Toyomaki, Y., Takiyoshi, N., Rokunohe, D., Nishikawa, Y., Korekawa, A., Matsuzaki, Y., Mitsuhashi, Y., Sawamura, D. Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation. Brit. J. Derm. 165: 1290-1292, 2011. [PubMed: 21801157] [Full Text: https://doi.org/10.1111/j.1365-2133.2011.10552.x]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/24/2008.
Kubo, A., Oura, Y., Hirano, T., Aoyama, Y., Sato, S., Nakamura, K., Takae, Y., Amagai, M. Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma. J. Derm. 40: 553-557, 2013. [PubMed: 23662636] [Full Text: https://doi.org/10.1111/1346-8138.12185]
Takahashi, K., Paladini, R. D., Coulombe, P. A. Cloning and characterization of multiple human genes and cDNAs encoding highly related type II keratin 6 isoforms. J. Biol. Chem. 270: 18581-18592, 1995. [PubMed: 7543104] [Full Text: https://doi.org/10.1074/jbc.270.31.18581]
Wilson, N. J., Messenger, A. G., Leachman, S. A., O'Toole, E. A., Lane, E. B., McLean, W. H. I., Smith, F. J. D. Keratin K6c mutations cause focal palmoplantar keratoderma. J. Invest. Derm. 130: 425-429, 2010. [PubMed: 19609311] [Full Text: https://doi.org/10.1038/jid.2009.215]