Alternative titles; symbols
HGNC Approved Gene Symbol: KRT3
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:52,789,685-52,796,117 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Meesmann corneal dystrophy 2 | 618767 | Autosomal dominant | 3 |
Cytokeratins (keratins) comprise a large family of peptides that combine to form the intermediate filaments (10-nm fibers) present in the cytoskeleton in epithelial cells. Type I cytokeratins are acidic and range from molecular weight 40 to 56.5 kD, whereas type II cytokeratins are neutral or basic and have molecular weights of 53 to 67 kD. Specific pairs of heterotypic keratin chains are coexpressed during the various stages of epithelial differentiation. This pattern of expression of cytokeratin pairs implies the existence of highly coordinated control of transcription. The gene for cytokeratin 3 (KRT3), a member of the type II subfamily, is expressed together with KRT12 (601687) during 'corneal-type' differentiation (Moll et al., 1982; Schermer et al., 1986; summary by Raimondi et al., 1994).
Using Northern blot analysis, Collin et al. (1992) detected expression of KRT3, which they called CK3, in gingiva, tongue, and cornea, but not in any other epithelial tissues examined.
The KRT3 gene is approximately 6.5 kb long and encodes one of the largest cytokeratin proteins (64 kD) (summary by Raimondi et al., 1994).
By fluorescence in situ hybridization, Raimondi et al. (1994) mapped the KRT3 gene to chromosome 12q12-q13. All type II keratin genes mapped to that time had been assigned to chromosome 12 where they appeared to be organized into one homotypic cluster.
Meesmann corneal dystrophy (MECD2; 618767) is an autosomal dominant disorder characterized by fragility of the anterior corneal epithelium where the KRT12 and KRT3 genes are specifically expressed. Cytoplasmic densities demonstrated in Meesmann corneal dystrophy (Tremblay and Dube, 1982) are reminiscent of the tonofilament clumping seen in other dominant keratin disorders. Furthermore, in K12 knockout mice, a complete loss of the K3/K12 cytoskeleton results in extreme fragility of corneal keratinocytes (Kao et al., 1996). Irvine et al. (1997) postulated that dominant-negative mutations in keratins K3 and K12 might cause Meesmann corneal dystrophy. They indeed found such mutations. In a family from Northern Ireland, they demonstrated linkage between KRT3 and this form of corneal dystrophy, and identified a heterozygous mutation (E509K; 148043.0001) in the KRT3 gene.
In affected members of a Taiwanese family with MECD2, Chen et al. (2005) identified a heterozygous missense mutation in the KRT3 gene (R503P; 148043.0002). The mutation segregated with the disease was not found in unaffected members of the family or in 50 controls.
In affected members of a Polish family with MECD2, Szaflik et al. (2008) identified a heterozygous missense mutation in the KRT3 gene (E498V; 148043.0003). The mutation, which segregated with the disease, was not found in unaffected family members or in 100 Polish controls.
Chen et al. (2015) identified a c.250C-T transition in exon 1 of the KRT3 gene, resulting in an arg84-to-trp substitution (R84W), in a 60-year-old man with Meesmann corneal dystrophy. This mutation was the first potentially causative mutation in the KRT3 head domain to be reported. Functional studies were not performed. The variant was not identified in 200 control chromosomes, but was present in 80/66,638 Europeans (0.1%) and 186/10,380 Africans (1.8%) in the ExAC database, with an overall minor allele frequency (MAF) of 0.0076 per the dbSNP and 1000 Genomes databases. The authors considered this a variant of uncertain significance.
In a family in Northern Ireland, Irvine et al. (1997) demonstrated that members with Meesmann corneal dystrophy (MECD2; 618767) were heterozygous for a 1525G-A transition in the KRT3 gene, resulting in a glu509-to-lys (E509K) substitution. This purine transition was a potential CpG deamination mutation. An identical CpG mutation in the analogous residue of the KRT2 gene (600194) is the most frequent cause of ichthyosis bullosa of Siemens (146800).
In affected members of a Taiwanese family with Meesmann corneal dystrophy (MECD2; 618767) in whom no disease-causing mutation was identified in the KRT12 gene, Chen et al. (2005) identified a heterozygous 1508G-C transversion (c.1508G-C, NM_057088) in exon 7 of the KRT3 gene, resulting in a predicted arg503-to-pro (R503P) substitution within the highly conserved helix termination motif of the rod domain 2B. The mutation completely segregated with the disease phenotype in the family. The mutation created a novel restriction site for BstXI, which was absent in the unaffected family members and in 50 controls. The 12-year-old proband presented with a history of foreign body sensation and mild blurred vision for 1 to 2 years in both eyes; following the diagnosis of MECD, another family member was found to be affected.
In affected members of a Polish family with Meesmann corneal dystrophy (MECD2; 618767) in whom no mutation was identified in the KRT12 gene, Szaflik et al. (2008) identified a heterozygous 1493A-T transversion in exon 7 (c.1493A-T, NM_057088) of the KRT3 gene, predicting a glu498-to-val (E498V) substitution within the highly conserved helix termination motif of the rod domain 2B. The mutation was identified by direct sequencing of the KRT3 gene and confirmed by PCR-RFLP analysis. The mutation segregated with the disease in the family and was not found in 100 Polish controls. The proband was identified by typical clinical appearance of corneal microcysts during a routine eye examination. He and 3 other affected members of the family had no symptoms of MECD.
Chen, J. L., Lin, B. R., Gee, K. M., Gee, J. A., Chung, D.-W. D., Frausto, R. F., Deng, S. X., Aldave, A. J. Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy. Molec. Vision 21: 1378-1386, 2015. [PubMed: 26788030]
Chen, Y.-T., Tseng, S.-H., Chao, S.-C. Novel mutations in the helix termination motif of keratin 3 and keratin 12 in 2 Taiwanese families with Meesmann corneal dystrophy. Cornea 24: 928-932, 2005. [PubMed: 16227835] [Full Text: https://doi.org/10.1097/01.ico.0000159732.29930.26]
Collin, C., Ouhayoun, J.-P., Grund, C., Franke, W. W. Suprabasal marker proteins distinguishing keratinizing squamous epithelia: cytokeratin 2 polypeptides of oral masticatory epithelium and epidermis are different. Differentiation 51: 137-148, 1992. [PubMed: 1282112] [Full Text: https://doi.org/10.1111/j.1432-0436.1992.tb00690.x]
Irvine, A. D., Corden, L. D., Swensson, O., Swensson, B., Moore, J. E., Frazer, D. G., Smith, F. J. D., Knowlton, R. G., Christophers, E., Rochels, R., Uitto, J., McLean, W. H. I. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy. Nature Genet. 16: 184-187, 1997. [PubMed: 9171831] [Full Text: https://doi.org/10.1038/ng0697-184]
Kao, W. W.-Y., Liu, C.-Y., Converse, R. L., Shiraishi, A., Kao, C. W.-C., Ishizaki, M., Doetschman, T., Duffy, J. Keratin 12-deficient mice have fragile corneal epithelia. Invest. Ophthal. Vis. Sci. 37: 2572-2584, 1996. [PubMed: 8977471]
Moll, R., Franke, W. W., Schiller, D. L., Geiger, B., Krepler, R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 31: 11-24, 1982. [PubMed: 6186379] [Full Text: https://doi.org/10.1016/0092-8674(82)90400-7]
Raimondi, E., Moralli, D., De Carli, L., Ceratto, N., Balzaretti, M., Leube, R., Collin, C., Romano, V. Assignment of the human cytokeratin 3 gene (KRT3) to 12q12-q13 by FISH. Cytogenet. Cell Genet. 66: 162-163, 1994. [PubMed: 7510223] [Full Text: https://doi.org/10.1159/000133690]
Schermer, A., Galvin, S., Sun, T.-T. Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests limbal location of corneal epithelial stem cells. J. Cell Biol. 103: 49-62, 1986. [PubMed: 2424919] [Full Text: https://doi.org/10.1083/jcb.103.1.49]
Szaflik, J. P., Oldak, M., Maksym, R. B., Kaminska, A., Pollak, A., Udziela, M., Ploski, R., Szaflik, J. Genetics of Meesmann corneal dystrophy: a novel mutation in the keratin 3 gene in an asymptomatic family suggests genotype-phenotype correlation. Molec. Vision 14: 1713-1718, 2008. [PubMed: 18806880]
Tremblay, M., Dube, I. Meesmann's corneal dystrophy: ultrastructural features. Canad. J. Ophthal. 17: 24-28, 1982. [PubMed: 6979375]