Alternative titles; symbols
HGNC Approved Gene Symbol: CDH3
SNOMEDCT: 720856002;
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:68,645,310-68,733,771 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | Ectodermal dysplasia, ectrodactyly, and macular dystrophy | 225280 | Autosomal recessive | 3 |
| Hypotrichosis, congenital, with juvenile macular dystrophy | 601553 | Autosomal recessive | 3 |
Cadherins, such as CDH3, are integral membrane glycoproteins responsible for calcium-dependent cell-cell adhesion.
Nose and Takeichi (1986) identified a novel cadherin cell adhesion molecule, P-cadherin, expressed in mouse placenta.
Using mouse P-cadherin as probe, Shimoyama et al. (1989) cloned human CDH3 from an epidermoid carcinoma cell line (A431) cDNA library. The deduced 829-amino acid protein contains a signal sequence, a transmembrane region, 4 cysteine residues in the extracellular domain, and 3 N-linked glycosylation sites. CDH3 shares 82% sequence homology with the mouse protein and 67% homology with uvomorulin (CDH1; 192090). Northern blot analysis revealed a 3.2-kb transcript in A431 cells, but not in human placenta. Western blot analysis of A431 cells and transfected NIH 3T3 cells revealed an apparent molecular mass of more than 116 kD.
The E-cadherin (CDH1) and P-cadherin genes are tightly linked on chromosome 8 of the mouse (Hatta et al., 1991). Since the human CDH1 locus is on 16q22.1, the P-cadherin gene is probably in the same location. Kremmidiotis et al. (1998) mapped the human CDH3 gene to 16q22.1 using somatic cell hybrid panels. They demonstrated that 5 cadherin genes (CDH1; CDH3; CDH5, 601120; CDH8, 603008; and CDH11, 600023) are clustered in the 16q21-q22.1 region.
Shimoyama et al. (1989) found that CDH3 transfected into NIH 3T3 cells was expressed at the cell-cell border. Cells expressing CDH3 also adhered to one another more tightly than the parental cell line.
Soler et al. (2002) found high levels of P-cadherin in human milk. Immunohistochemistry revealed apical staining for P-cadherin in epithelial cells of lactating tissue, and the staining pattern was similar to that of a secreted protein. Staining was not found at cell-cell borders. Western blot analysis of human milk revealed a truncated, soluble 80-kD P-cadherin protein containing the extracellular domain but not the intracellular domain.
Overexpression of P-cadherin has been associated with proliferative lesions of high histologic grade, decreased cell polarity, and poor survival of patients with breast cancer. In vitro studies showed that it can be upregulated by the antiestrogen drug ICI 182,780, suggesting that the lack of estrogen receptor-alpha (ESRA; 133430) signaling may responsible for the aberrant P-cadherin overexpression and for its role in inducing breast cancer cell invasion and migration. Albergaria et al. (2010) showed that ICI 182,780 was able to increase P-cadherin promoter activity, inducing high levels of the active chromatin marker H3 lysine-4 dimethylation (H3K4me2). Albergaria et al. (2010) also showed that CEBPB (189965) was able to upregulate CDH3 promoter activity in breast cancer cells. Moreover, the expression of P-cadherin and CEBPB were highly associated in human breast carcinomas and linked with a worse prognosis in breast cancer patients. The authors concluded that epigenetic upregulation of P-cadherin by ICI 182,780 in MCF-7/AZ breast cancer cells occurs through chromatin remodeling at the CDH3 promoter, bringing forward the growing evidence that ESRA signaling abrogation by antiestrogens may be able to induce the expression of ESRA-repressed genes which, in the appropriate cell biology context, may contribute to a breast cancer cell invasion phenotype.
Mescher et al. (2017) found that low epidermal PAR3 (PARD3; 606745) and high P-cadherin expression correlated with human melanoma progression. Elevated P-cadherin expression in primary tumors was associated with reduced survival of melanoma patients. Expression of P-cadherin in metastases was low compared with its expression in primary tumors. The findings suggested that P-cadherin is important in initiation, growth, and progression of primary melanoma, but that melanoma cells may become independent of P-cadherin-mediated effects after metastatic colonization. Mice with loss of epidermal Par3 expression underwent melanocyte dedifferentiation, motility, and hyperplasia. In an autochthonous melanoma model, inactivation of Par3 resulted in increased tumor formation and lung metastasis. Loss of Par3 specifically in keratinocytes upregulated surface P-cadherin that was essential to promote melanocyte proliferation and the phenotypic switch toward dedifferentiation. Mescher et al. (2017) concluded that reduced keratinocyte Par3 function permits a P-cadherin-dependent niche for melanocyte transformation, invasion, and metastasis and that PAR3 has an extrinsic tumor-suppressive function.
Hypotrichosis with Juvenile Macular Dystrophy
Hypotrichosis with juvenile macular dystrophy (HJMD; 601553) is a rare recessive disorder. Sprecher et al. (2001) studied 4 large consanguineous HJMD families with 11 affected individuals, belonging to the Druze population in northern Israel. By homozygosity mapping, they assigned the disease locus to 16q22.1, the region containing the CDH3 gene. Searching this positional candidate, they found a common homozygous deletion in exon 8 of the CDH3 gene (114021.0001) in all 4 families.
Ectodermal Dysplasia, Ectrodactyly, and Macular Dystrophy Syndrome
Kjaer et al. (2005) studied 2 families with ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS; 225280) and identified homozygous mutations in CDH3 in affected individuals: a missense mutation (114021.0003) and a deletion (114021.0004), respectively.
In 4 Druze families, Sprecher et al. (2001) demonstrated that hypotrichosis with juvenile macular dystrophy (HJMD; 601553) was caused by homozygous deletion of a guanine nucleotide in exon 8 at position 981 from the translation start site (ATG) of CDH3. The 981delG mutation abolished the recognition site for NlaIII and was predicted to result in a frameshift that introduced a premature termination codon 23 residues downstream of the mutation site. Expression of mRNA and of CDH3 protein was reduced in the skin of these patients.
In a family with hypotrichosis with juvenile macular dystrophy (HJMD; 601553), Indelman et al. (2002) found a homozygous G-to-A transition at nucleotide 1508 in exon 11 of the CDH3 gene, resulting in a substitution of his for arg at position 503 of the P-cadherin sequence (R503H). The amino acid substitution affected a highly conserved residue and was predicted to alter a Ca(2+)-binding domain of P-cadherin. This was the first pathogenic missense mutation reported in CDH3.
In affected individuals with ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS; 225280) from the consanguineous Danish family previously reported by Albrectsen and Svendsen (1956), Kjaer et al. (2005) identified homozygosity for a 965A-T transversion in exon 8 of the CDH3 gene, resulting in an asn322-to-ile (N322I) substitution in a highly conserved motif predicted to affect Ca(2+) binding and to alter specificity of the cell-cell binding function. The unaffected first-cousin parents were both heterozygous for the mutation.
In an affected individual with ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome (EEMS; 225280) from the Brazilian family previously reported by Balarin Silva et al. (1999), Kjaer et al. (2005) identified homozygosity for a 1-bp deletion (829delG) in exon 7 of the CDH3 gene, introducing a frameshift and a premature stop codon at residue 295, predicted to result in a nonfunctional protein lacking both its intracellular and membrane-spanning domains and its extracellular cadherin repeats 3-5. The parents, a brother, and a son of the proband were all heterozygous for the mutation. The brother exhibited minimal symptoms, having mild bilateral syndactyly between fingers 1, 2, 3, and 4 and small, widely spaced teeth, but an unremarkable ophthalmologic and hair examination.
Albergaria, A., Ribeiro, A. S., Pinho, S., Milanezi, F., Carneiro, V., Sousa, B., Sousa, S., Oliveira, C., Machado, J. C., Seruca, R., Paredes, J., Schmitt, F. ICI 182,780 induces P-cadherin overexpression in breast cancer cells through chromatin remodelling at the promoter level: a role for C/EBP beta in CDH3 gene activation. Hum. Molec. Genet. 19: 2554-2566, 2010. [PubMed: 20385540] [Full Text: https://doi.org/10.1093/hmg/ddq134]
Albrectsen, B., Svendsen, I. B. Hypotrichosis, syndactyly, and retinal degeneration in two siblings. Acta Derm. Venereol. 36: 96-101, 1956. [PubMed: 13372143]
Balarin Silva, V., Simoes, A. M., Marques-de-Faria, A. P. EEM syndrome: report of a family and results of a ten-year follow-up. Ophthal. Genet. 20: 95-99, 1999. [PubMed: 10420194] [Full Text: https://doi.org/10.1076/opge.20.2.95.2290]
Hatta, M., Miyatani, S., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Takeichi, M. Genomic organization and chromosomal mapping of the mouse P-cadherin gene. Nucleic Acids Res. 19: 4437-4441, 1991. [PubMed: 1886768] [Full Text: https://doi.org/10.1093/nar/19.16.4437]
Indelman, M., Bergman, R., Lurie, R., Richard, G., Miller, B., Petronius, D., Ciubutaro, D., Leibu, R., Sprecher, E. A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with juvenile macular dystrophy. J. Invest. Derm. 119: 1210-1213, 2002. [PubMed: 12445216] [Full Text: https://doi.org/10.1046/j.1523-1747.2002.19528.x]
Kjaer, K. W., Hansen, L., Schwabe, G. C., Marques-de-Faria, A. P., Eiberg, H., Mundlos, S., Tommerup, N., Rosenberg, T. Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). J. Med. Genet. 42: 292-298, 2005. [PubMed: 15805154] [Full Text: https://doi.org/10.1136/jmg.2004.027821]
Kremmidiotis, G., Baker, E., Crawford, J., Eyre, H. J., Nahmias, J., Callen, D. F. Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity. Genomics 49: 467-471, 1998. [PubMed: 9615235] [Full Text: https://doi.org/10.1006/geno.1998.5281]
Mescher, M., Jeong, P., Knapp, S. K., Rubsam, M., Saynisch, M., Kranen, M., Landsberg, J., Schlaak, M., Mauch, C., Tuting, T., Niessen, C. M., Iden, S. The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. J. Exp. Med. 214: 339-358, 2017. [PubMed: 28096290] [Full Text: https://doi.org/10.1084/jem.20160596]
Nose, A., Takeichi, M. A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos. J. Cell Biol. 103: 2649-2658, 1986. [PubMed: 3539943] [Full Text: https://doi.org/10.1083/jcb.103.6.2649]
Shimoyama, Y., Yoshida, T., Terada, M., Shimosato, Y., Abe, O., Hirohashi, S. Molecular cloning of a human Ca(2+)-dependent cell-cell adhesion molecule homologous to mouse placental cadherin: its low expression in human placental tissues. J. Cell Biol. 109: 1787-1794, 1989. [PubMed: 2793940] [Full Text: https://doi.org/10.1083/jcb.109.4.1787]
Soler, A. P., Russo, J., Russo, I. H., Knudsen, K. A. Soluble fragment of P-cadherin adhesion protein found in human milk. J. Cell. Biochem. 85: 180-184, 2002. [PubMed: 11891861]
Sprecher, E., Bergman, R., Richard, G., Lurie, R., Shalev, S., Petronius, D., Shalata, A., Anbinder, Y., Leibu, R., Perlman, I., Cohen, N., Szargel, R. Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nature Genet. 29: 134-136, 2001. [PubMed: 11544476] [Full Text: https://doi.org/10.1038/ng716]