Alternative titles; symbols
HGNC Approved Gene Symbol: KRT6A
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38) : 12:52,487,176-52,493,257 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Pachyonychia congenita 3 | 615726 | Autosomal dominant | 3 |
Keratin 6A (K6A) is the dominant K6 isoform. Takahashi et al. (1995) screened human genomic and skin cDNA libraries with probes derived from the K6B gene (148042), and isolated clones containing the full-length gene and cDNA predicted to encode K6a. As many as 6 different human K6 protein isoforms that are highly related at the gene structure, nucleotide sequence, and predicted amino acid sequence levels were identified. Takahashi et al. (1995) proposed an evolutionary model in which the multiplicity of human K6 genes is explained by successive gene duplication events. They confirmed that K6A is clearly the dominant K6 isoform in skin tissue samples and cultured epithelial cell lines and that the various isoforms are differentially regulated within and between epithelial tissue types.
Tyner et al. (1985) provided information on the structure of a type II keratin gene. A recent duplication in the basic keratin gene family gave rise to 2 copies of the human K6 gene. One of the copies is expressed at very low levels and may be at a still unextinguished step on the way to becoming a traditional pseudogene.
Takahashi et al. (1995) determined that the KRT6A gene contains 9 exons.
Rosenberg et al. (1991) assigned the KRT6A gene to chromosome 12 by use of Southern blot analysis of somatic cell hybrids. By in situ hybridization of metaphase chromosomes, they demonstrated that the KRT6A gene is located in region 12q12-q14.
In affected members of a Slovenian family segregating pachyonychia congenita described as the Jadassohn-Lewandowsky type (PC3; 615726), Bowden et al. (1995) identified heterozygosity for a mutation in the KRT6A gene (148041.0001).
Terrinoni et al. (2001) identified 3 novel mutations (148041.0002-148041.0004) and 2 previously identified mutations (see, e.g., 148041.0001) in the KRT6A gene in patients with pachyonychia congenita.
Smith et al. (2005) identified keratin mutations in 30 probands from the International Pachyonychia Congenita Research Registry, 17 of whom had mutations in the KRT6A gene (see, e.g., 148041.0001 and 148041.0005-148041.0008).
In a 32-year-old Chinese woman with pachyonychia congenita, Du et al. (2012) identified heterozygosity for a splice site mutation in the KRT6A gene (148041.0009). Her 7-year-old daughter, who had only focal plantar hyperkeratosis with no nail or hand involvement, was also heterozygous for the mutation.
In a patient with sporadic PC3, Wilson et al. (2014) identified a heterozygous nonsense mutation in the KRT6A gene (E461X; 148041.0010).
Wong et al. (2000) found that K6-null mice have changes in the oral mucosa resembling those of pachyonychia congenita. They speculated on why the mice lacked obvious alterations in nail morphology, the conspicuous feature in pachyonychia congenita.
Wojcik et al. (2001) generated mice deficient in both K6a and K6b. The majority of K6a/K6b double-null mice died of starvation within the first 2 weeks of life. The starvation was due to a localized disintegration of the dorsal tongue epithelium, which resulted in the buildup of a plaque of cell debris that severely impaired feeding. However, about 25% of K6a/K6b double-null mice survived to adulthood and had normal hair and nails. Wojcik et al. (2001) identified a third K6 gene expressed in hair follicles, K6hf (609025), and suggested that its presence offers an explanation for the absence of hair and nail defects in K6a/K6b double-null mice.
Wilson et al. (2014) cited this mutation as c.516_518delCAA (Asn172del).
In a Slovenian family, Bowden et al. (1995) observed pachyonychia congenita of the Jadassohn-Lewandowsky type (PC3; 615726) in the grandfather, father, and daughter. The father and daughter had classic changes with thickened nails, palmoplantar keratoderma, and leukokeratosis of the tongue. The grandfather had only minor nail changes and mild keratoderma (raising the possibility of somatic and germinal mosaicism). No mutation was found in KRT16 and KRT17 in which mutations had been found in other patients with pachyonychia congenita. They identified heterozygosity for a 3-bp deletion (AAC) in exon 1 of the K6A gene, which removed a highly conserved asparagine residue from position 8 (Asn8del) of the 1A helical domain. The mutation was present in heterozygous state.
Terrinoni et al. (2001) found this mutation, which they designated N171del (Asn171del), in 1 familial and 2 sporadic cases of PC. The analogous mutation in the KRT4 gene (123940.0001) was reported in 2 cases of white sponge nevus (Rugg et al., 1995). This mutation is consistent with DNA polymerase slippage during replication of 3 tandem CAA repeats present in exon 1 of several type II keratin genes, including KRT4 and KRT6A.
In 3 familial and 3 sporadic cases of pachyonychia congenita, Smith et al. (2005) identified heterozygosity for the Asn171del mutation in the KRT6A gene.
In a patient with sporadic pachyonychia congenita (PC3; 615726), Terrinoni et al. (2001) identified a c.520T-G transversion in the KRT6A gene that resulted in a phe174-to-val (F174V) amino acid substitution. This mutation is F10V in the 1A domain of the protein.
In a patient with sporadic PC (PC3; 615726), Terrinoni et al. (2001) identified a c.1414G-to-A transition in the KRT6A gene that resulted in a glu472-to-lys (E472K) amino acid substitution. This mutation is E117K in the 2B domain of the protein.
In a patient with sporadic PC (PC3; 615726), Terrinoni et al. (2001) reported a c.1406T-G transversion in the KRT6A gene that resulted in a leu469-to-arg (L469R) amino acid substitution. This mutation is L114R in the 2B domain of the protein.
In a patient with sporadic pachyonychia congenita (PC3; 615726), Smith et al. (2005) identified heterozygosity for a c.1406T-C transition in the KRT6A gene, resulting in a leu469-to-pro (L469P) substitution in the highly conserved helix termination motif of the 2B domain.
In a patient with sporadic pachyonychia congenita (PC3; 615726), Smith et al. (2005) identified heterozygosity for a c.512A-G transition in the KRT6A gene, resulting in an asn171-to-ser (N171S) substitution in the highly conserved helix initiation motif of the 1A domain.
In a patient from a family with pachyonychia congenita (PC3; 615726), Smith et al. (2005) identified heterozygosity for a c.513C-A transversion in the KRT6A gene, resulting in an asn171-to-lys (N171K) substitution in the highly conserved helix initiation motif of the 1A domain.
In 2 patients with sporadic pachyonychia congenita (PC3; 615726), Smith et al. (2005) identified heterozygosity for a c.521T-C transition in the KRT6A gene, resulting in a phe174-to-ser (F174S) substitution in the highly conserved helix initiation motif of the 1A domain.
In a 32-year-old Chinese woman with pachyonychia congenita (PC3; 615726), Du et al. (2012) identified heterozygosity for an A-to-C transversion at position -2 in intron 8 of the KRT6A gene (IVS8-2A-C), resulting in an 11-bp deletion (c.1460_1470del) at the beginning of exon 9, due to activation of a downstream splice acceptor site. The deletion was predicted to cause a frameshift resulting in a premature termination codon (Ser487PhefsTer72). The proband had toenail thickening, plantar hyperkeratosis with fissuring, and mild focal palmar hyperkeratosis but no fingernail changes; she also exhibited oral leukokeratosis, chapped lips, and fissured tongue. Her 7-year-old daughter, who was also heterozygous for the splice site mutation, had focal plantar hyperkeratosis, fissured tongue, and gingivitis, but no nail or hand involvement. Both patients reported hyperhidrosis of the hands and feet.
In a patient (family 21) with sporadic pachyonychia congenita-3 (PC3; 615726), Wilson et al. (2014) identified a heterozygous c.1381G-T transversion in the KRT6A gene, resulting in a glu461-to-stop (E461X) substitution at the start of the helix termination motif in the 2B domain and a protein lacking the helix termination motif and tail domain.
Bowden, P. E., Haley, J. L., Kansky, A., Rothnagel, J. A., Jones, D. O., Turner, R. J. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nature Genet. 10: 363-365, 1995. [PubMed: 7545493] [Full Text: https://doi.org/10.1038/ng0795-363]
Du, Z.-F., Xu, C.-M., Zhao, Y., Liu, W.-T., Chen, X.-L., Chen, C.-Y., Fang, H., Ke, H.-P., Zhang, X.-N. Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma. Europ. J. Derm. 22: 476-480, 2012. [PubMed: 22668561] [Full Text: https://doi.org/10.1684/ejd.2012.1773]
Rosenberg, M., Fuchs, E., Le Beau, M. M., Eddy, R. L., Shows, T. B. Three epidermal and one simple epithelial type II keratin genes map to human chromosome 12. Cytogenet. Cell Genet. 57: 33-38, 1991. [PubMed: 1713141] [Full Text: https://doi.org/10.1159/000133109]
Rugg, E. L., McLean, W. H. I., Allison, W. E., Lunny, D. P., Macleod, R. I., Felix, D. H., Lane, E. B., Munro, C. S. A mutation in the mucosal keratin K4 is associated with oral white sponge nevus. Nature Genet. 11: 450-452, 1995. [PubMed: 7493030] [Full Text: https://doi.org/10.1038/ng1295-450]
Smith, F. J. D., Liao, H., Cassidy, A. J., Stewart, A., Hamill, K. J., Wood, P., Joval, I., van Steensel, M. A. M., Bjorck, E., Callif-Daley, F., Pals, G., Collins, P., Leachman, S. A., Munro, C. S., McLean, W. H. I. The genetic basis of pachyonychia congenita. J. Invest. Derm. Symp. Proc. 10: 21-30, 2005. [PubMed: 16250206] [Full Text: https://doi.org/10.1111/j.1087-0024.2005.10204.x]
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]
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]
Tyner, A., Eichman, M., Fuchs, E. The sequence of a type II keratin gene expressed in human skin: conservation of structure among all intermediate filament genes. Proc. Nat. Acad. Sci. 82: 4683-4687, 1985. [PubMed: 2410904] [Full Text: https://doi.org/10.1073/pnas.82.14.4683]
Wilson, N. J., O'Toole, E. A., Milstone, L. M., Hansen, C. D., Shepherd, A. A., Al-Asadi, E., Schwartz, M. E., McLean, W. H., Sprecher, E., Smith, F. J. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Brit. J. Derm. 171: 343-355, 2014. [PubMed: 24611874] [Full Text: https://doi.org/10.1111/bjd.12958]
Wojcik, S. M., Longley, M. A., Roop, D. R. Discovery of a novel murine keratin 6 (K6) isoform explains the absence of hair and nail defects in mice deficient for K6a and K6b. J. Cell Biol. 154: 619-630, 2001. [PubMed: 11489919] [Full Text: https://doi.org/10.1083/jcb.200102079]
Wong, P., Colucci-Guyon, E., Takahashi, K., Gu, C., Babinet, C., Coulombe, P. A. Introducing a null mutation in the mouse K6-alpha and K6-beta genes reveals their essential structural role in the oral mucosa. J. Cell Biol. 150: 921-928, 2000. [PubMed: 10953016] [Full Text: https://doi.org/10.1083/jcb.150.4.921]