Alternative titles; symbols
HGNC Approved Gene Symbol: DSC3
SNOMEDCT: 724350009;
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:30,989,365-31,042,742 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Hypotrichosis and recurrent skin vesicles | 613102 | Autosomal recessive | 3 |
From a bladder carcinoma cell line cDNA library, Kawamura et al. (1994) cloned a human cDNA encoding a novel transmembrane protein. Sequence analysis revealed an open reading frame of 2,691 bp encoding a protein of 896 amino acids. Sequence comparisons showed significant homology to desmocollins, intercellular adhesion molecules belonging to the cadherin superfamily. The protein consisted of a signal peptide of 30 amino acids, a precursor segment of 105 amino acids, and a mature protein of 761 amino acids. Antibodies recognizing the predicted mature adhesion molecule of the protein stained antigens along the cell boundaries of normal human keratinocytes resembling the pattern of desmosome localization. Kawamura et al. (1994) concluded that the clone represented a new member of the desmocollin family and tentatively referred to it as desmocollin type 4.
King et al. (1995) used the designation DSC3 for a gene encoding a desmocollin present in human foreskin epidermis and stated that the gene is identical to that encoding the desmocollin isolated from a bladder carcinoma cell line and called DSC4 by Kawamura et al. (1994). King et al. (1995) stated that the cDNA sequence showed 67% amino acid identity with the original human desmocollin, designated DSC2 (125645), and 52% amino acid identity with DSC1 (125643). By in situ hybridization studies, they showed that DSC1 was not present in any of the nonkeratinizing human epithelia, such as buccal mucosa, cervix, and esophagus, whereas all these internal epithelia expressed DSC2 and DSC3 and were present in most of the living layers of tissues, including the basal layers.
Amagai et al. (1995) used fluorescence in situ hybridization to demonstrate that the DSC3 gene maps to chromosome 18q12 in the same region as the DSC2 gene.
King et al. (1995) likewise mapped the DSC3 gene to chromosome 18 by PCR analysis of rodent/human somatic cell hybrids.
In affected members of a consanguineous Afghan family with hypotrichosis and recurrent skin vesicles (HYPTSV; 613102) mapping to chromosome 18q12.1, Ayub et al. (2009) identified homozygosity for a nonsense mutation in the DSC3 gene (L710X; 600271.0001). The unaffected parents and 3 healthy sibs were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls.
In a 5-year-old Egyptian boy with hypotrichosis and recurrent skin blisters, Onoufriadis et al. (2020) identified homozygosity for a nonsense mutation in the DSC3 gene (L727X; 600271.0002) for which his unaffected consanguineous parents and sister were heterozygous.
Chen et al. (2008) generated mice carrying a conditional Dsc3-null allele and a K14-Cre transgene that was constitutively active in the basal layer of the epidermis beginning at embryonic day 14. All newborn mutant pups showed histologically detectable blisters in the epidermis, but only 10% of pups showed macroscopic skin blistering, which was usually lethal within a few hours of birth. All mutant mice that reached adulthood showed severe skin lesions, ranging from severe epidermal hyperplasia due to an increase in basal cell proliferation to complete loss of the epidermis in large sections of the skin. Histologic examination of skin lesions in newborn mutant mice revealed intraepidermal blistering with acantholysis (cell-cell separation) just above the basal cell layer, with lateral separation of basal keratinocytes in later stages. Electron microscopy showed half-desmosomes in the plasma membranes of keratinocytes at the bottom and the roof of the blister, suggesting impaired desmosome function as the cause of the defect. In vitro mechanical testing demonstrated significantly less stress resistance in cell sheets generated from mutant keratinocytes than controls, and the fragility was shown to be caused by loss of cell-cell adhesion rather than lysis. The mutant mice also showed hair loss on their backs at weaning age, which began on the head and progressed toward the tail. The hair eventually grew back, but patches of hair loss occurred in older mice, and some mice completely lost their hair. The timing and pattern suggested a defect in anchorage of telogen follicles; histologic analysis confirmed that the mutant mice were losing telogen hair, and showed acantholysis in the anchoring epithelial cell layers surrounding the telogen club. The authors concluded that DSC3 is required for normal desmosome function and maintenance of tissue integrity in the interfollicular epidermis.
In affected members of a consanguineous Afghan family with hypotrichosis and recurrent skin vesicles (HYPTSV; 613102), Ayub et al. (2009) identified homozygosity for a 2129T-G transversion in exon 14 of the DSC3 gene, resulting in a leu710-to-ter (L710X) substitution at the junction of the transmembrane and the C-terminal cytoplasmic domain, predicted to cause premature termination and nonsense mediated decay of the mRNA or instability of the truncated protein. The unaffected parents and 3 healthy sibs were heterozygous for the mutation, which was not found in 100 unrelated ethnically matched controls.
In a 5-year-old Egyptian boy with hypotrichosis and recurrent skin blisters (HYPTSV; 613102), Onoufriadis et al. (2020) identified homozygosity for a c.2180T-G transversion in the DSC3 gene, resulting in a leu727-to-ter (L727X) substitution at a residue within the intracellular region of the protein. His unaffected consanguineous parents and sister were heterozygous for the mutation. Immunofluorescence microscopy of patient skin revealed complete absence of DSC3 labeling, consistent with nonsense-mediated RNA decay.
Amagai, M., Wang, Y., Minoshima, S., Kawamura, K., Green, K. J., Nishikawa, T., Shimizu, N. Assignment of the human genes for desmocollin 3 (DSC3) and desmocollin 4 (DSC4) to chromosome 18q12. Genomics 25: 330-332, 1995. [PubMed: 7774948] [Full Text: https://doi.org/10.1016/0888-7543(95)80154-e]
Ayub, M., Basit, S., Jelani, M., Rehman, F. U., Iqbal, M., Yasinzai, M., Ahmad, W. A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. Am. J. Hum. Genet. 85: 515-520, 2009. [PubMed: 19765682] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.015]
Chen, J., Den, Z., Koch, P. J. Loss of desmocollin 3 in mice leads to epidermal blistering. J. Cell Sci. 121: 2844-2849, 2008. [PubMed: 18682494] [Full Text: https://doi.org/10.1242/jcs.031518]
Kawamura, K., Watanabe, K., Suzuki, T., Yamakawa, T., Kamiyama, T., Nakagawa, H., Tsurufuji, S. cDNA cloning and expression of a novel human desmocollin. J. Biol. Chem. 269: 26295-26302, 1994. [PubMed: 7929347]
King, I. A., Sullivan, K. H., Bennett, R., Jr., Buxton, R. S. The desmocollins of human foreskin epidermis: identification and chromosomal assignment of a third gene and expression patterns of the three isoforms. J. Invest. Derm. 105: 314-321, 1995. [PubMed: 7665906] [Full Text: https://doi.org/10.1111/1523-1747.ep12319935]
Onoufriadis, A., Ahmed, N., Bessar, H., Guy, A., Liu, L., Marantzidis, A., Kesidou, E., Papanikolaou, M., Simpson, M. A., Mellerio, J. E., Lee, J. Y. W., McGrath, J. A. Homozygous nonsense mutation in DSC3 resulting in skin fragility and hypotrichosis. J. Invest. Derm. 140: 1285-1288, 2020. [PubMed: 31790667] [Full Text: https://doi.org/10.1016/j.jid.2019.10.015]