Alternative titles; symbols
ORPHA: 79400;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Epidermolysis bullosa simplex 2C, localized | 619594 | Autosomal dominant | 3 | KRT5 | 148040 |
A number sign (#) is used with this entry because localized epidermolysis bullosa-2C (EBS2C) is caused by heterozygous mutation in the KRT5 gene (148040) on chromosome 12q13.
Another form of localized EBS, EBS1C (131800), is caused by mutation in the KRT14 gene (148066).
Localized epidermolysis bullosa simplex-2C (EBS2C) is an autosomal dominant skin disorder with intraepidermal blistering after minor trauma mainly restricted to hands and feet beginning in infancy. Nails may be thick and dystrophic (summary by Has et al., 2020). Localized epidermolysis bullosa simplex has previously been known as the Weber-Cockayne type.
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Reviews
Has et al. (2020) reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility.
Chan et al. (1993) studied 2 unrelated multigenerational families with EBS Weber-Cockayne type who carried mutations in the KRT5 gene. Affected family members had mild blistering of palmar and plantar skin upon physical trauma. Ultrastructural examination revealed features typical of EBS, including vacuoles and wavy tonofilament aggregates in basal cells.
Yasukawa et al. (2002), Oldak et al. (2011), Gonzalez-Cantero et al. (2017), and Vahidnezhad et al. (2019) described individuals with mild localized EBS phenotypes who were heterozygous for an E170K mutation in the KRT5 gene; these individuals had family members carrying the E170K mutation in either compound heterozygosity or homozygosity who had a more severe phenotype. See MOLECULAR GENETICS.
In an American family of Northern European ancestry (EBS-WC-Fo), Bonifas et al. (1991) found linkage of the Weber-Cockayne form of EBS to markers D12S14 and D12S17, loci that map physically very near the keratin-5 gene on chromosome 12.
The genetic heterogeneity of the Weber-Cockayne form of EBS was indicated by the findings of McKenna et al. (1992) in 2 families: 1 family showed linkage to markers on chromosome 17 flanking the keratin-14 gene and was excluded from linkage to markers on chromosome 12 flanking the keratin-5 gene. A second family showed linkage to the region containing the keratin 5 gene and was excluded from linkage to the keratin-14 gene.
The transmission pattern of EBS2C in the families reported by Chan et al. (1993) was consistent with autosomal dominant inheritance.
In affected members of 2 unrelated families with Weber-Cockayne EBS, Chan et al. (1993) identified a heterozygous mutation in the K5 gene (I161S; 148040.0003). Ehrlich et al. (1995) identified the I161S mutation in 6 of 13 families with the Weber-Cockayne type of EB simplex. The high frequency of this mutation suggested either a hotspot or founder effect.
Chan et al. (1994) identified mutations in the K5 gene (148040.0004; 148040.0005) in patients with Weber-Cockayne EBS.
Pfendner et al. (2005) identified a heterozygous KRT5 mutation (I161S; 148040.0003) in a patient with blistering of the hands and feet. The patient's affected mother carried the same mutation.
E170K Mutation
Yasukawa et al. (2002) reported an unusual Japanese family with EBS and 2 mutations in the KRT5 gene, resulting in phenotypic variability. The proband was a man with classic generalized EBS, diagnosed as Koebner type, manifest as blistering of the trunk and extremities, improvement with age, and cytolysis within basal keratinocytes on biopsy. Genetic analysis identified compound heterozygosity for the E170K (148040.0020) and E418K (148040.0021) mutations in the KRT5 gene. His paternal uncle, who had blisters restricted to the palms and soles consistent with localized EBS, was heterozygous for the E170K mutation. The proband's deceased father and paternal grandmother, who were putatively heterozygous for the E170K mutation, also reportedly had localized blistering of the hands and feet. In contrast, 2 unaffected family members were heterozygous for the E418K substitution, implying that it is not pathogenic in isolation. In vitro functional expression studies showed that cells transfected with either mutation developed small ball-like filament aggregates, indicating a disruption of the keratin network, although the effect was more pronounced for the E170K mutation. Expression of both mutant proteins exacerbated the clumping and resulted in significantly more disruption than either alone. These findings were consistent with the marked phenotypic and genotypic variability observed in this family.
Oldak et al. (2011) reported a clinically heterogeneous EBS family with the E170K mutation in the KRT5 gene. The proband was a 10-year-old girl who had widespread skin fragility and blistering from birth at sites of minor mechanical trauma. Blistering improved slightly with age, but severe blisters continued to form on the hands and feet, and occasionally on trunk and neck. She was diagnosed with EBS Koebner type (generalized intermediate). Her parents had blisters restricted to soles of the feet since their teenage years after extensive walking; they were diagnosed with localized EBS. The mother's deceased father and uncle also had foot blisters after walking. The patient's 13-year-old sister reported no symptoms. The E170K mutation was found in homozygosity in the proband, and in heterozygosity in her parents and sister. Oldak et al. (2011) concluded that, together with the findings of Yasukawa et al. (2002), the KRT5 E170K mutation alone causes a mild phenotype, and exhibits a gene dosage effect consistent with the phenomenon of 'partial dominance.' Oldak et al. (2011) noted that partial dominance had also been reported with the KRT14 mutation M119I (148066.0010).
Gonzalez-Cantero et al. (2017) reported a family in which the proband was a 7-year-old girl who had blisters and erosions from birth on palms, soles, and other trauma-prone sites. Isolated blisters were present on the trunk and neck, as well as mildly dystrophic toenails, micronychia of the little finger, and horizontal ridging consistent with onychomadesis of the other toenails. Her parents had no blisters or erosions but had mildly dystrophic toenails, micronychia and thickening of the nail plate of the second toe, and horizontal ridging of the great toenail. Mutation analysis detected homozygosity for the E170K KRT5 mutation in the daughter and heterozygosity in the parents. Gonzalez-Cantero et al. (2017) noted that the E170K mutation exhibits 'partial dominance.'
Vahidnezhad et al. (2019) reported a 32-year-old woman from a consanguineous family (family 1) of Iranian origin with Kurdish ethnicity who had trauma-induced blistering and erosions noted a few days after birth. Blisters were multiple and widespread and were particularly severe on the plantar aspects of the feet, accompanied by plantar keratoderma. Nail dystrophy with subungual bullae leading to nail loss was also present. There was mucosal involvement including all areas of oral mucosa including the tongue. Although the parents were described as 'clinically unaffected,' they were noted to have mild blistering of the feet after strenuous and prolonged walking, and showed evidence of perturbed intermediate filament assembly in basal keratinocytes on electron microscopy. The proband was homozygous for the KRT5 E170K mutation, which was carried in heterozygosity by each of her parents.
Kim et al. (2017) screened 52 Australian patients with EBS for mutations in the KRT5 and KRT14 genes and identified 32 different mutations in 39 pedigrees. The authors found that mutations causing localized EBS occurred sporadically across the KRT5 and KRT14 peptides. Mutations resulting in generalized severe EBS were most commonly clustered at the helix boundary motifs, the helix initiation (HIP) and termination (HTP) regions, which are critical for normal keratin formation. In most other cases phenotypes correlated with the location of the mutations and were in agreement with previous reports.
Bonifas, J. M., Rothman, A. L., Epstein, E. H., Jr. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science 254: 1202-1205, 1991. [PubMed: 1720261] [Full Text: https://doi.org/10.1126/science.1720261]
Bonifas, J. M., Rothman, A. L., Epstein, E., Jr. Linkage of epidermolysis bullosa simplex to probes in the region of keratin gene clusters on chromosomes 12q and 17q. (Abstract) Clin. Res. 39: 503A only, 1991.
Chan, Y., Yu, Q.-C., LeBlanc-Straceski, J., Christiano, A., Pulkkinen, L., Kucherlapati, R. S., Uitto, J., Fuchs, E. Mutations in the non-helical linker segment L1-2 of keratin 5 in patients with Weber-Cockayne epidermolysis bullosa simplex. J. Cell Sci. 107: 765-774, 1994. [PubMed: 7520042] [Full Text: https://doi.org/10.1242/jcs.107.4.765]
Chan, Y.-M., Yu, Q.-C., Fine, J.-D., Fuchs, E. The genetic basis of Weber-Cockayne epidermolysis bullosa simplex. Proc. Nat. Acad. Sci. 90: 7414-7418, 1993. [PubMed: 7688477] [Full Text: https://doi.org/10.1073/pnas.90.15.7414]
Ehrlich, P., Sybert, V. P., Spencer, A., Stephens, K. A common keratin 5 gene mutation in epidermolysis bullosa simplex: Weber-Cockayne. J. Invest. Derm. 104: 877-879, 1995. [PubMed: 7537780] [Full Text: https://doi.org/10.1111/1523-1747.ep12607050]
Gonzalez-Cantero, A., Sanchez-Moya, A. I., Perez-Hortet, C., Martinez-Lorenzo, E., Gomez-Dorado, B., Schoendorff-Ortega, C. 'Nails only' phenotype and partial dominance of p.glu170lys mutation in a family with epidermolysis bullosa simplex. Pediat. Derm. 34: e205-e206, 2017. [PubMed: 28425111] [Full Text: https://doi.org/10.1111/pde.13146]
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Kim, E. N., Harris, A. G., Bingham, L. J., Yan, W., Su, J. C., Murrell, D. F. A review of 52 pedigrees with epidermolysis bullosa simplex identifying ten novel mutations in KRT5 and KRT14 in australia. Acta Derm. Venereol. 97: 1114-1119, 2017. [PubMed: 28561874] [Full Text: https://doi.org/10.2340/00015555-2715]
McKenna, K. E., Hughes, A. E., Bingham, E. A., Nevin, N. C. Linkage of epidermolysis bullosa simplex to keratin gene loci. J. Med. Genet. 29: 568-570, 1992. [PubMed: 1381443] [Full Text: https://doi.org/10.1136/jmg.29.8.568]
Oldak, M., Szczecinska, W., Przybylska, D., Maksym, R. B., Podgorska, M., Wozniak, K., Ploski, R., Kowalewski, C. Gene dosage effect of p.Glu170Lys mutation in the KRT5 gene in a Polish family with epidermolysis bullosa simplex. J. Derm. Sci. 61: 64-67, 2011. [PubMed: 21144712] [Full Text: https://doi.org/10.1016/j.jdermsci.2010.11.002]
Pfendner, E. G., Sadowski, S. G., Uitto, J. Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. J. Invest. Derm. 125: 239-243, 2005. [PubMed: 16098032] [Full Text: https://doi.org/10.1111/j.0022-202X.2005.23818.x]
Vahidnezhad, H., Youssefian, L., Daneshpazhooh, M., Mahmoudi, H., Kariminejad, A., Fischer, J., Christiansen, J., Schneider, H., Guy, A., Liu, L., McGrath, J. A., Has, C., Uitto, J. Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 'knock-out'. Matrix Biol. 83: 48-59, 2019. [PubMed: 31302245] [Full Text: https://doi.org/10.1016/j.matbio.2019.07.002]
Yasukawa, K., Sawamura, D., McMillan, J. R., Nakamura, H., Shimizu, H. Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. J. Biol. Chem. 277: 23670-23674, 2002. [PubMed: 11973334] [Full Text: https://doi.org/10.1074/jbc.M200974200]