Alternative titles; symbols
HGNC Approved Gene Symbol: KRT2
SNOMEDCT: 254169002, 763768001;
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,644,558-52,652,211 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Ichthyosis bullosa of Siemens | 146800 | Autosomal dominant | 3 |
Keratins are the major gene product of keratinocytes and form the intermediate filament cytoskeletal network in these cells. Intermediate filament proteins consist of a central alpha-helical rod domain flanked by nonhelical sequences of varying size and composition. Keratin proteins fall into 2 classes on the basis of their electrophoretic properties and sequence similarities. One member of each class is required to form the heterodimeric coiled-coil precursor which through both lateral and longitudinal associations form the mature keratin intermediate filament. The major epidermal keratins of the type I class are KRT9 (607606), KRT10 (148080), KRT14 (148066), and KRT16 (148067); the major epidermal keratins of the type II class are KRT1 (139350), KRT2, KRT5 (148040), KRT6A (148041), and KRT6B (148042). The expression of individual keratins is specific both for body site and for stage of differentiation of the epidermal keratinocyte. Keratinocytes in the basal layer express KRT5 and KRT14. Upon differentiation and migration to the spinous layer, these genes are downregulated and the expression of KRT1 and KRT10 is induced. In cells of the upper spinous layer, KRT2 and KRT9 are expressed. Although the expression of KRT9 is limited to palmoplantar epidermis, KRT2 is expressed not only in this tissue but also in other regions, notably the epidermis covering the knee, thigh, and groin. It is not known whether these keratins simply replace their respective type I or type II counterpart in the preexisting KRT1/KRT10 network or dimerize with another, as yet undiscovered keratin partner. The other major epidermal keratins, KRT6 and KRT16, are normally expressed in the outer root sheath of the hair follicle and in palmoplantar epidermis.
Keratin 2e is a protein of molecular weight 65.8 kD encoded by a 2.6-kb mRNA species. Collin et al. (1992) determined the sequence of the KRT2e cDNA.
Smith et al. (1998) determined the genomic organization and complete sequence of the KRT2 gene, which consists of 9 exons spanning 7,634 bp of DNA.
Presumably the KRT2 gene maps to 12q11-q13, the site of the other class II genes, such as KRT1 and KRT5. By high-resolution radiation hybrid mapping, Smith et al. (1998) localized the gene to the interval between microsatellite markers D12S368 and a specific CHLC marker.
Mutations in the basal cell-specific keratins KRT5 and KRT14 are found in patients with epidermolysis bullosa simplex (e.g., 131900); mutations in the differentiation-specific keratins KRT1 and KRT10 have been found in patients with epidermolytic hyperkeratosis (113800); and mutations in the palmoplantar-specific keratin KRT9 have been found in patients with epidermolytic palmoplantar keratoderma (144200). Rothnagel et al. (1994) and McLean et al. (1994) demonstrated mutations in the KRT2 gene in patients with ichthyosis bullosa of Siemens (IBS; 146800). Kremer et al. (1994) also found mutations in the KRT2 gene in patients with IBS and in a patient with a phenotypically related, if not identical, disorder, ichthyosis exfoliativa (see 146800).
Smith et al. (1998) detected several intragenic polymorphisms in the KRT2 gene, including an 18-bp duplication in exon 1, corresponding to the V1 domain of the K2e polypeptide. Two novel mutations, N192Y in the 1A domain and E482K in the 2B domain of K2e, were found in families with IBS.
In an Asian family with ichthyosis bullosa of Siemens (146800; originally diagnosed as epidermolytic hyperkeratosis), Rothnagel et al. (1994) identified a G-to-T transversion at basepair 1512 of the published sequence (Collin et al., 1992) of the KRT2 gene, resulting in a glutamic acid to aspartic acid substitution at residue 117 in the highly conserved C terminal of the rod domain. (According to Rothnagel et al. (1994), the residue designated 117 corresponds to codon 493 of the published sequence.)
In 4 families with autosomal dominant inheritance of ichthyosis bullosa of Siemens (146800) and in 1 sporadic case of this disorder, Rothnagel et al. (1994) found a G-to-A transition at nucleotide 1510 resulting in a lysine for glutamic acid substitution at residue 117 of the KRT2 protein. Thus in a total of 6 instances, the mutation occurred in the same codon, GAG (glu); the mutation was to GAT in 1 family and to AAG in the 5 others. (According to Rothnagel et al. (1994), the residue designated 117 corresponds to codon 493 of the published sequence.)
In 2 unrelated British families with ichthyosis bullosa of Siemens, McLean et al. (1994) found a glu493-to-lys mutation in the highly conserved LLEGEE helix termination motif, producing a change to LLEGKE. The mutation was predicted to be highly detrimental to keratin filament assembly and/or functional integrity. A G-to-A transition at nucleotide 1510 of the cDNA sequence occurred in a CpG dinucleotide.
Kremer et al. (1994) identified the E493K mutation in a family described as having ichthyosis exfoliativa (see 146800), originally reported by Vakilzadeh and Kolde (1991), and in yet another Dutch family with ichthyosis bullosa of Siemens.
In a large family with ichthyosis bullosa of Siemens in 8 members spanning 3 generations, Basarab et al. (1999) identified the E493K mutation in the KRT2 gene. The patients showed blistering, superficial peeling of the skin, and localized lichenified hyperkeratosis, mainly confined to the limbs. Phenotypic variation with some individuals exhibiting unusual clinical features was also observed. The index patient was erythrodermic at birth and subsequently developed a widespread pustular eruption. She also had hypertrichosis of the limbs, as did an affected female first cousin. Basarab et al. (1999) found that E493K is by far the most frequent mutation in this disorder.
In a Dutch family with ichthyosis bullosa of Siemens (146800), Kremer et al. (1994) found a heterozygous transversion of adenosine to cytosine at nucleotide 593. This transversion led to the substitution of a proline for a glutamine at codon 187 (numbering according to Collin et al. (1992)) of the predicted protein sequence.
In a 4-year-old Korean boy, Yang et al. (1997) observed a sporadic case of ichthyosis bullosa of Siemens (IBS; 146800) and demonstrated a thr485-to-pro amino acid substitution in the highly conserved consensus motif at the end of the 2-B rod domain segment of the keratin 2 chain. The disease phenotype was consistent with the inappropriate substitution of proline near the end of the rod domain, because it was situated near the predicted molecular overlap region of coiled-coil molecules, which is critical for the maintenance of the structural integrity of keratin intermediate filaments. The patient had brownish, wrinkled, and encrusted hyperkeratosis and blistering over the entirety of his trunk and limbs, especially on flexural areas, beginning at the age of 100 days. Blistering was more pronounced during summer and could be provoked by mild trauma. Erythroderma had never been present. Light microscopic examination showed epidermolytic hyperkeratosis limited to the upper part of the epidermis.
In a family with ichthyosis bullosa of Siemens (IBS; 146800), Smith et al. (1998) identified an asn192-to-tyr substitution in the KRT2 gene.
In a family with ichthyosis bullosa of Siemens (IBS; 146800), Smith et al. (1998) identified a glu482-to-lys substitution in the KRT2 gene.
In a family with ichthyosis bullosa of Siemens (IBS; 146800), Takizawa et al. (2000) identified an A-to-G transition at nucleotide position 607 of the KRT2 gene, resulting in an asn192-to-asp substitution.
In a patient with ichthyosis bullosa of Siemens (IBS; 146800), Whittock et al. (2001) reported a heterozygous C-to-A transversion at nucleotide 576 of the KRT2 gene that resulted in an asn192-to-lys (N192K) amino acid substitution in the conserved 1A helix initiation peptide.
Basarab, T., Smith, F. J. D., Jolliffe, V. M. L., McLean, W. H. I., Neill, S., Rustin, M. H. A., Eady, R. A. J. Ichthyosis bullosa of Siemens: report of a family with evidence of a keratin 2e mutation, and a review of the literature. Brit. J. Derm. 140: 689-695, 1999. [PubMed: 10233323] [Full Text: https://doi.org/10.1046/j.1365-2133.1999.02772.x]
Collin, C., Moll, R., Kubicka, S., Ouhayoun, J.-P., Franke, W. W. Characterization of human cytokeratin 2, an epidermal cytoskeletal protein synthesized late during differentiation. Exp. Cell Res. 202: 132-141, 1992. [PubMed: 1380918] [Full Text: https://doi.org/10.1016/0014-4827(92)90412-2]
Kremer, H., Zeeuwen, P., McLean, W. H. I., Mariman, E. C. M., Lane, E. B., van de Kerkhof, P. C. M., Ropers, H.-H., Steijlen, P. M. Ichthyosis bullosa of Siemens is caused by mutations in the keratin 2e gene. J. Invest. Derm. 103: 286-289, 1994. [PubMed: 8077693] [Full Text: https://doi.org/10.1111/1523-1747.ep12394414]
McLean, W. H. I., Morley, S. M., Lane, E. B., Eady, R. A. J., Griffiths, W. A. D., Paige, D. G., Harper, J. I., Higgins, C., Leigh, I. M. Ichthyosis bullosa of Siemens--a disease involving keratin 2e. J. Invest. Derm. 103: 277-281, 1994. [PubMed: 7521371] [Full Text: https://doi.org/10.1111/1523-1747.ep12394307]
Rothnagel, J. A., Traupe, H., Wojcik, S., Huber, M., Hohl, D., Pittelkow, M. R., Saeki, H., Ishibashi, Y., Roop, D. R. Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nature Genet. 7: 485-490, 1994. [PubMed: 7524919] [Full Text: https://doi.org/10.1038/ng0894-485]
Smith, F. J. D., Maingi, C., Covello, S. P., Higgins, C., Schmidt, M., Lane, E. B., Uitto, J., Leigh, I. M., McLean, W. H. I. Genomic organization and fine mapping of the keratin 2e gene (KRT2E): K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of Siemens. J. Invest. Derm. 111: 817-821, 1998. [PubMed: 9804344] [Full Text: https://doi.org/10.1046/j.1523-1747.1998.00371.x]
Takizawa, Y., Akiyama, M., Nagashima, M., Shimizu, H. A novel asparagine-aspartic acid mutation in the rod 1A domain in keratin 2e in a Japanese family with ichthyosis bullosa of Siemens J. Invest. Derm. 114: 193-195, 2000. [PubMed: 10620137] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00817.x]
Vakilzadeh, F., Kolde, G. Autosomal dominant ichthyosis exfoliativa. Brit. J. Derm. 124: 191-194, 1991. [PubMed: 2004005] [Full Text: https://doi.org/10.1111/j.1365-2133.1991.tb00432.x]
Whittock, N. V., Ashton, G. H. S., Griffiths, W. A. D., Eady, R. A. J., McGrath, J. A. New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of Siemens. Brit. J. Derm. 145: 330-335, 2001. [PubMed: 11531804] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.04327.x]
Yang, J.-M., Lee, S., Bang, H.-D., Kim, W.-S., Lee, E.-S., Steinert, P. M. A novel threonine-to-proline mutation at the end of 2B rod domain in the keratin 2e chain in ichthyosis bullosa of Siemens. J. Invest. Derm. 109: 116-118, 1997. [PubMed: 9204966] [Full Text: https://doi.org/10.1111/1523-1747.ep12276775]