Alternative titles; symbols
HGNC Approved Gene Symbol: KRT6B
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38) : 12:52,446,651-52,452,146 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Pachyonychia congenita 4 | 615728 | Autosomal dominant | 3 |
By screening a human skin cDNA library with probes derived from the KRT6A gene (148041), Takahashi et al. (1995) cloned KRT6B, which they designated K6B. Like other K6 proteins, the deduced K6B protein contains 564 amino acids, and it has a calculated molecular mass of about 60 kD. K6B shares at least 97.6% identity with other K6 proteins. Northern blot analysis detected a 2.3-kb K6B transcript in cultured epithelial cells.
Takahashi et al. (1995) determined that the KRT6B gene contains 9 exons.
Rosenberg et al. (1991) assigned the KRT6B gene to chromosome 12 by Southern blot analysis of somatic cell hybrids.
Stumpf (2020) mapped the KRT6B gene to chromosome 12q13.13 based on an alignment of the KRT6B sequence (GenBank BC034535) with the genomic sequence (GRCh38).
Type I and type II keratins, encoded by genes on chromosome 17 and chromosome 12, respectively, form the heteropolymeric intermediate filament cytoskeleton, which is the main stress-bearing structure within epithelial cells. Smith et al. (1998) identified KRT6B as the expression partner of keratin-17 (KRT17; 148069). Coexpression of these genes was confirmed by in situ hybridization and immunohistochemical staining.
Smith et al. (1998) described a family diagnosed with pachyonychia congenita of the Jackson-Lawler type in which the KRT17 locus (148069) on 17q was excluded and linkage to the type II keratin cluster on 12q was obtained (maximum lod = 3.31 at theta = 0.0). By molecular analysis of candidate keratins, Smith et al. (1998) identified the first reported missense mutation in KRT6B (E472K; 148042.0001) and found that KRT6B is the expression partner of KRT17, analogous to the KRT6A/KRT16 pair. The results revealed the hitherto unknown role of the KRT6B isoform in epithelial biology, as well as genetic heterogeneity in pachyonychia congenita (PC4; 615728).
In 2 families (families 29 and 30) segregating pachyonychia congenita, Smith et al. (2005) described heterozygosity for the same E472K mutation in the KRT6B gene that had been identified in a Dutch family by Smith et al. (1998). Haplotype analysis showed that family 29 had an independent occurrence of the mutation; haplotype analysis was not possible in family 30 because of lack of samples, but the family was not of Dutch ancestry. Samuelov et al. (2020) determined that 55% of PC4 patients with no fingernail involvement had the E472K mutation.
In 9 of 84 families with pachyonychia congenita recruited through the International Pachyonychia Congenita Research Registry, Wilson et al. (2014) identified heterozygous mutations in the KRT6B gene, including 1 novel mutation (L469R; 148042.0002). The authors noted that the analogous mutation had been reported in the KRT6A gene (148041.0004).
In a 9-year-old Chinese girl with delayed onset of PC4, Guo et al. (2014) identified a heterozygous missense mutation (G499S; 148042.0003) in the KRT6B gene.
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.
In a family with autosomal dominant pachyonychia congenita of the Jackson-Lawler type (PC4; 615728), Smith et al. (1998) described a heterozygous 1459G-A mutation that abolished a BseRI restriction site and predicted a glu472-to-lys (E472K) substitution in the conserved helix termination motif of KRT6B. This mutation conformed to the CpG deamination model of mutation and the analogous mutation had been seen in a number of other type II keratins where this sequence is conserved. The clinical features pictured included focal palmoplantar keratoderma on the pressure points of the feet, and similar focal palmar callosities. Hypertrophic nail dystrophy affected all fingernails and toenails. Steatocystomas, on the skin of the trunk, for example, were widespread in postpubescent affected individuals. Mild lingual hyperkeratosis was observed on the margins of the tongue. Smith et al. (1998) stated that oral leukokeratosis is prominent in Jadassohn-Lewandowski PC, since KRT16 and KRT6A are strongly expressed in these epithelia, but is not commonly observed in Jackson-Lawler PC. These observations indicated that expression of KRT6B, like KRT17, is topographically restricted in oral and lingual epithelia.
In affected members of 2 families (families 29 and 30) segregating pachyonychia congenita, described as the Jackson-Lawler type, Smith et al. (2005) identified heterozygosity for the same E472K mutation in the KRT6B gene that had been identified in a Dutch family by Smith et al. (1998). Haplotype analysis showed that family 29 had an independent occurrence of the mutation; haplotype analysis was not possible in family 30 because of lack of samples, but the family was not of Dutch ancestry.
In affected members of 3 families (families 38-40) segregating pachyonychia congenita, Wilson et al. (2014) identified heterozygosity for the E472K mutation in the KRT6B gene.
In affected members of a family (family 37) segregating pachyonychia congenita (PC4; 615728), Wilson et al. (2014) identified a heterozygous c.1406T-G transversion in the KRT6B gene, resulting in a leu496-to-arg (L496R) substitution.
In a 9-year-old Chinese girl with delayed-onset pachyonychia congenita, Guo et al. (2014) identified a heterozygous c.1495G-A transversion in exon 9 of the KRT6B gene, resulting in a gly499-to-ser (G499S) substitution in the tail domain. No mutation was detected in her parents or in 100 unrelated controls.
Guo, K., Xiao, S., Geng, S., Feng, Y., Zhang, D., Zhou, P., Zhang, Y. Delayed-onset pachyonychia congenita caused by a novel mutation in the V2 domain of keratin 6b. (Letter) J. Derm. 41: 108-109, 2014. [PubMed: 24354895] [Full Text: https://doi.org/10.1111/1346-8138.12349]
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]
Samuelov, L., Smith, F. J. D., Hansen, C. D., Sprecher, E. Revisiting pachyonychia congenita: a case-cohort study of 815 patients. Brit. J. Derm. 182: 738-746, 2020. [PubMed: 31823354] [Full Text: https://doi.org/10.1111/bjd.18794]
Smith, F. J. D., Jonkman, M. F., van Goor, H., Coleman, C. M., Covello, S. P., Uitto, J., McLean, W. H. I. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum. Molec. Genet. 7: 1143-1148, 1998. [PubMed: 9618173] [Full Text: https://doi.org/10.1093/hmg/7.7.1143]
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]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/09/2020.
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., O'Toole, E. A., Milstone, L. M., Hansen, C. D., Shepherd, A. A., Al-Asadi, E., Schwartz, M. E., McLean, W. H. I., Sprecher, E., Smith, F. J. D. 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]